doi: 10.1161/01.RES.0000041680.43270.F8
© 2002 American Heart Association, Inc.
Reviews |
Dance Band on the Titanic
Biomechanical Signaling in Cardiac Hypertrophy
From the Children’s Hospital and Research Foundation (M.S.), Division of Molecular Cardiovascular Biology, Cincinnati, Ohio; the Department of Bioengineering (A.M.), Institute for Molecular Medicine, La Jolla, Calif; and the Department of Developmental Biology and Anatomy (T.K.B.), University of South Carolina, Columbia, SC.
Correspondence to Thomas K. Borg, Department of Developmental Biology and Anatomy, University of South Carolina, Columbia, SC 29208. E-mail borg{at}med.sc.edu
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Abstract |
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 Top Abstract IntroductionOrganization of the ECMConclusionsReferences |
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Biomechanical signaling is a complex interaction of both intracellular and extracellular components. Both passive and active components are involved in the extracellular environment to signal through specific receptors to multiple signaling pathways. This review provides an overview of extracellular matrix, specific receptors, and signaling pathways for biomechanical stimulation in cardiac hypertrophy.
Key Words: mechanical signaling • cardiac hypertrophy • extracellular matrix
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Introduction |
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While all cells, tissues, and organisms depend on external mechanical inputs to maintain their phenotypes, cardiac cells are also constantly generating active forces of contraction. Mechanical forces are intimately linked to chemical signals that lead to many interrelated modifications both inside and outside the various cell types of the heart. Outside the cells, these modifications include dynamic restructuring of the extracellular matrix (ECM) and its signaling components and alterations in the quantity and type of cell surface receptors. Within the cell, changes occur in signaling proteins, contractile apparatus, and cytoskeleton. Because these structural alterations prompt alterations in mechanical properties of the cells and ECM, they result in a redistribution of mechanical stimuli until a new (mechanical and biological) equilibrium is achieved. This dynamic system works well in the physiological adaptation to a variety of signals that result in normal cardiac growth or development; however, when this equilibrium goes out of balance, the result can be pathological growth and abnormal physiology. In this review, we focus on the components that regulate biomechanosignaling in the cardiac myocyte and their integration.
Mechanical stress provides critical information for maintenance of myocardial structure and function. Because dynamic changes in stress occur with every contraction/relaxation cycle as well as with short- and long-term hemodynamic alterations, this information must be integrated using multiple sensors. Chronic elevation of force exerted on cardiomyocytes prompts signaling reactivity and remodeling that transforms the structural characteristics and physical properties of the myocardium altering the balance of forces between different regions and components of the tissue. Increased physical stress on the heart can be normal and beneficial, but pathological conditions such as hypertension, ischemia, or contractile abnormalities that increase stress excessively lead to maladaptive remodeling that may precede the onset of heart failure. Because of the close interplay between the myocytes and the ECM, it is not surprising that cellular and extracellular remodeling tends to occur in tandem, such as fibrosis that accompanies pressure-overload hypertrophy.
Mechanotransduction—the transformation of a mechanical stimulus into cellular responses—is a hallmark of myocardial cells. Mechanical stress and strain activate a panoply of signaling pathways too numerous to be adequately addressed in this review. Accordingly, the overview presented here is not intended to be exhaustive or highly detailed. Rather than reiterate the perspective of recent related reviews,1–3 the purpose herein will be to concentrate on signaling pathways associated with structural remodeling in response to altered mechanical loading of the myocardium and to provide an integrated view of how mechanical stimulation cascades into promotion of cellular growth, remodeling, and survival.
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Organization of the ECM |
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Intimately associated with mechanical force are the components of the ECM and their organization in the interstitium. Initially described as structural molecules with a passive role in force transmission, the ECM is now recognized to play a more dynamic role in signaling cellular growth, apoptosis, and remodeling. The ECM is now viewed as a composite network of large molecular weight collagens, proteoglycans, glycosaminoglycans, and glycoproteins that act both as structural components and in the regulation of cell function.4 In addition, a subset of ECM components called matricellular proteins has been proposed.5 These are critical in the regulation of cell growth, migration, apoptosis, and phenotype and include growth factors, cytokines, and proteases. These in turn regulate cell-matrix interactions, playing an important role in mechanical signaling.
The principal structural components of the ECM are the collagens, which form a three-dimensional network interconnecting myocytes to each other and the vasculature. The development of this elastic stress-tolerant collagenous network is intimately associated with the generation and transmission of mechanical forces to and from the myocytes.6–8 In addition to interstitial collagen, collagen type IV is localized to the basement membrane and is probably important in the regulation of cell volume. Type IV collagen has a chicken-wire arrangement that changes with the contraction of the myocyte and helps maintain cell shape.9 Thus, the ECM contains both active and latent signaling components that are essential in homeostasis, remodeling in response to pathophysiological signals (growth factors), activation of cell surface receptors (integrins), and remodeling of the collagenous network.
Mechanical Interactions Between Myocytes and the ECM
Cardiac cells are constantly loaded by external forces while simultaneously developing internal contractile forces. The two principal mechanical pathways are the transmission of contractile forces via the sarcomeric lattice, cytoskeleton, and ECM to the ventricular chambers; and the responses of cardiac cells to external hemodynamic loads and to internal stresses developed by the neighboring cells and ECM. These internal and external forces must balance each other to maintain the myocardium in physical equilibrium.
Because the cells and ECM of the myocardium are organized in a three-dimensional hierarchy that supports a nonhomogeneous distribution of stresses, different components of the ECM hierarchy may be structurally in parallel or in series with the cellular components of the myocardium. For example, diastolic fiber stresses are partitioned between myocytes and the collagen network acting structurally in parallel so that they share the total load. The combined passive fiber stiffness of myocardium has been attributed predominantly to intracellular structures, notably titin, at low sarcomere lengths.10 This giant protein or its binding partners in the cytoskeleton and sarcomere may therefore act as intracellular sensors of fiber stress or strain.11
At longer sarcomere lengths, parallel collagen fibers bear an increasing fraction of the axial stress as coiled perimysial fibers untwist and straighten.12 It is unlikely that these large fibers ever become completely straight even at pathophysiologically high filling pressures.13 Conversely, during systole, active fiber shortening below the stress-free sarcomere length is opposed by the viscoelasticity of the collagens and proteoglycans.14 While compression of parallel coiled perimysial fibers stores elastic energy that is released during early filling, there is also a contribution from forces distributed in series between the cells and matrix.15,16 Elastic energy is developed in transverse collagen "ties" that are strained by the large thickening and transverse shearing deformations of the ventricular walls as myocytes shorten and myofiber lamellae reorient during systole.17,18 (Note that the endomysial ties are often called "struts," a term that is more correctly reserved for compression-bearing members of a structure.)
Although transverse systolic strains can be large, the usual assumption has been that myofilaments develop significant contractile stresses predominantly or exclusively along their principal axis in the direction of the myofiber axis. However, even simple considerations of crossbridge geometry suggest that up to 30% of the crossbridge force could be directed perpendicular to the fiber axis.19 How these forces integrate to resultant cellular stresses depends primarily on the sarcomere lattice structure. Tonically activated isolated rabbit septum stretched equibiaxially generates active stresses in the transverse direction that can exceed 40% of those in the fiber direction.20 Allowing for this property in a biomechanical model of whole ventricular mechanics reconciles significant disparities with experimentally observed wall strains in models that assume myocyte tension generation is uniaxial.21,22 While recent studies suggest that changes in transverse myofilament lattice spacing are unlikely to be a key mechanism of length-dependent activation,19,23 they are likely to influence transverse stress development.
Stresses transverse to the myofibers are transmitted from myocyte to myocyte at the level of the z-line via endomysial collagen ties. In view of the concentration of signaling complexes clustered at the costamere, where the z-disk meets membrane-associated ECM receptors, this site is a prime candidate for mechanical sensing. Wang and colleagues24 suggested that the integrin focal-adhesion cytoskeleton complex is a mechanically sensitive signaling organelle, and substantial evidence now supports this conjecture. Indeed, in vitro studies of stretch responses in micropatterned neonatal cardiac myocytes engineered to grow on deformable surfaces in elongated parallel-fibered morphologies have shown that myocyte hypertrophic responses to stretch may be significantly more sensitive to loads applied perpendicular than parallel to the myofilament axis.25,26
Physical interactions between the ECM and the myocytes contribute to the development of the residual stresses that remain in the myocardium when external loads are removed.27,28 Compressive residual stresses shorten endocardial sarcomeres in the unloaded ventricle and are balanced by tensile residual stresses that prestretch epicardial fibers.29 This provides a mechanism for maintaining transmural uniformity of stress and sarcomere length at end-diastole,30 and changes in residual stress resulting from nonuniform hypertrophy have been described as an adaptive response to hemodynamic overload in arteries. Yet the most striking alterations in myocardial residual stresses have been developmental responses to ECM gene mutations in the tightskin mouse, Tsk, and the osteogenesis imperfecta murine, oim.31,32 The increase in myocardial collagen content in the Tsk myocardium was associated with an almost complete loss of residual strain, whereas the disruption of type I collagen assembly in the myocardium of mice homozygous for the oim mutation was associated with a 3-fold increase. These observations suggest that nonuniform regional hypertrophy in intact myocardium is mediated via ECM-dependent pathways, either directly via cell-matrix signals, or indirectly via their effects on local stresses, or both.
Force Generation in the ECM
The arrangement of collagen ECM into the three-dimensional network surrounding and interconnecting myocytes forms a laminar myocardial organization33 with a well-described formation and function.17,34 However, little notice has been given to the interstitial space between the lamellae. It normally contains fluid moving from the capillaries and taken up by the lymphatic system. Lymphatic fluid includes several ECM components such as proteoglycans and glycosaminoglycans that affect interstitial pressure and viscosity. The electro-osmotic properties of the highly charged proteoglycans and glycosaminoglycans affect the mechanical properties of tissue because their sugar components have a high affinity for water, thereby increasing interstitial hydrostatic pressures and altering stress distributions between cells and matrix; however, their precise regulation and functional roles are poorly understood.35,36 Interstitial fluid movement is governed by several factors including collagen density. It is likely that as collagen density increases, resistance to interstitial fluid movement increases, increasing pressure gradients and altering the shear stresses applied to myocardial cells and the balance of forces within the myocardium (Figure).
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The nonmyocyte cellular components combined with the ECM can also generate forces that mechanically strain the matrix. Experimental models to test the hypothesis of force generation from the ECM primarily use fibroblasts seeded in collagen gels,37–39 which are allowed to "contract" over time. These studies have demonstrated that gel contraction can be stimulated by a wide variety of factors including growth factors (angiotensin II, insulin-like growth factor-1 [IGF-1], platelet-derived growth factor [PDGF]) and mast cells.40–42 Contraction can also be blocked by antibodies against integrins, matrix metalloproteases, and pharmacological interventions. While all of these factors are present in the heart during development and disease and could play a role in the exertion of mechanical force to cardiac myocytes, data directly demonstrating their role in vivo are lacking. They could be particularly important in postinfarction wound healing and subsequent chamber remodeling, by contributing to the balance of forces and signals that govern the tendency for scar contraction versus expansion.43
The arrangement of fibroblasts in the endomysial collagen is essential to the generation of mechanical force.44 Studies indicate that fibroblasts exist as a sheet of interconnected cells both in vivo and in vitro in collagen gels. In this arrangement, fibroblasts can transmit electrical or ionic signals via gap junctions and mechanical force by their receptor-mediated connections to the ECM. Interesting experiments have shown that if these connections are blocked, no mechanical force is generated.16 It would appear that if the fibroblasts are arranged as a sheet, they are more likely to resist as well as transmit mechanical force to the surrounding myocytes (Figure).
The role of proteases in the generation or redistribution of mechanical stresses in the ECM is relatively unexplored but of significant potential.45,46 From gel contraction experiments, matrix metalloproteases (MMPs) appear to be an essential component but with an undefined role. ADAMs (a disintegrin and metalloproteases) may also be essential in modification of the ECM in force generation. Other proteases may also contribute by the activation of latent factors such as growth factors or ECM components that would signal growth and thereby generate increased mechanical tension. Although several ECM components, such as fibronectin, have been shown to stimulate myocyte growth (hypertrophy), it is not clear whether this stimulation is as large molecular weight molecules or smaller molecular weight species that have been activated by proteolytic cleavage. Fibronectin may also act as a strain sensor itself by exposing cryptic binding sites as it unfolds under external forces.47
Receptors and the ECM
At least three classes of receptors are important in the inside-out and outside-in transmission of mechanical forces between the cells and ECM. They are found on both myocytes and fibroblasts. Integrins are the most well-recognized class of ECM receptor and have been recently reviewed.48,49 Integrins, which are heterodimers of 
and ß subunits, change with development, hypertrophy, and aging. The expression of integrins appears to be coordinated with specific ECM expression; however, in heart failure abnormal expression results, which contributes to altered mechanical properties.50–52 Integrin receptors are involved in signaling in both outside-in and inside-out manner on myocytes and fibroblasts.
A second class of receptors, discoidin domain receptor (DDR), is not well documented but could be significant, because they are transmembrane complexes, attaching specifically to collagen, and have tyrosine kinase motifs in the cytoplasmic domain.53 There are several isoforms of the DDR family that appear on both fibroblasts and myocytes. However, only DDR2 is found on fibroblasts. This appears to be a unique marker for these cells. A third class of receptors is the cadherins, which regulate cell-cell interaction.54 Although cadherins play a significant role in myocytes, their role in fibroblasts is not known. However, as fibroblasts within the collagen network appear to be interconnected, this class of receptor could play a significant role in force transmission between fibroblasts.
The arrangement and localization of receptors on the surface of fibroblasts and myocytes appear to be critical to force generation and transmission. In vitro studies show the localization of integrins to be primarily at focal adhesions. This connects the ECM components with the actin cytoskeleton and components of the signaling pathways.17 Structures analogous to focal adhesions are located in vivo near the sarcomeric Z band and connected to the ECM, cytoskeleton, and signaling complexes. Different from in vitro localization is the presence of the intercalated disk, which may also be important in force transmission and determining the partitioning of stresses between the cells and ECM.
In addition to acting as potentially important slow force generators that regulate the geometry and stress distributions of the myocardium, cardiac fibroblasts, which make up about two thirds of cardiac cells, also have the ability to sense, integrate and functionally respond to mechanical stimuli.55 They are also a source of autocrine/paracrine factors such as endothelin-1, tumor necrosis factor- (TNF-), and angiotensin II that are released in response to mechanical stimulation.56,57 In vitro studies have shown that induction of ECM gene expression in cardiac fibroblasts by stretch is differentially responsive to dynamic versus static, tensile versus compressive, and uniaxial versus biaxial stretching.58–60 Upstream, the initial activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) by stretch is substrate-dependent and integrin-specific.61
Autocrine/Paracrine Connections to MAPKs and JAK/STATs
Diverse signaling molecules are activated within minutes of acute mechanical stimulation. Multiple studies have also left no doubt that release of autocrine and paracrine factors amplifies the initial growth stimulus triggered by mechanical stretch. Angiotensin II, endothelin-1, vascular endothelial growth factor (VEGF), and transforming growth factor-ß have all been implicated in cardiac cellular hypertrophy in vitro62,63 and in vivo.63–67 These growth factors share the common property of directly or indirectly activating members of the mitogen-activated protein kinase (MAPK) family through Raf/Ras-dependent signaling pathways (see reviews1,68). MAPK regulation is an established archetype of complex amplification and crosstalk from years of cumulative studies.69 Briefly, MAPKs are serine/threonine kinases that target substrates in a multilayered signaling network composed of the MAPKs, the MAPK/ERK kinases (MEKs), and the MEK kinases (MEKKs). Among the MAPK superfamily, the ERKs, JNKs, and p38 kinases are well-known mediators of hypertrophic signaling in myocardial cells. MAPKs phosphorylate target substrates in the nucleus (eg, c-myc, c-jun, and ATF-2), leading to transcriptional reprogramming that is likely responsible, at least in part, for altered gene expression associated with hypertrophy.
MAPKs respond to a variety of activating stimuli originating from a diverse array of signaling pathways. For example, ERK can be activated by Raf via Ras, phospholipase C and protein kinase C, protein kinase A, and G protein—coupled receptors stimulated by bound receptors for hormones or growth factors.68,69 A different pathway involving integrin-FAK-Src-Ras signaling associated with mechanical stretch leads to p38 activation.70 Thus, although the necessity of the angiotensin II pathway for ERK and p38 activation after stretch has been questioned,71,72 plenty of alternative ways exist for these MAPKs to become involved in the response to mechanical stretch. For ERK, this includes the transmembrane glycoprotein gp130, which not only activates ERK but is also involved in regulation of the Janus-associated kinases (JAKs) and signal transducers and activators of transcription (STATs).
Like MAPKs, activation of the JAK/STAT cascade can be initiated by paracrine stimulation, although the receptors involved bind cytokine ligands such as cardiotrophin-1 or leukemia inhibitory factor.73,74 Mechanical stretch of cultured cardiomyocytes or pressure-overload banding both activate the JAK/STAT cascade.75,76 These factors signal through the common receptor component of the IL-6 family known as gp130, which is involved in cardiomyocyte hypertrophy and survival.77 Binding of ligands to the gp130 receptor prompts activation of JAK/STAT cascades associated with transcriptional reprogramming of important genes such as bcl-xl and vascular endothelial growth factor.78 Repression of the JAK/STAT cascade by suppressor of cytokine signaling-3 (SOCS-3) is important for providing the critical counterbalance to maintain appropriate signaling from these powerful hypertrophic pathways.79 Characterization of crosstalk between activators (ie, gp130) and repressors (ie, SOCS-3) of hypertrophic signaling provides fundamental information regarding how the cardiomyocyte response to hypertrophic signaling is controlled. But cytokine-mediated hypertrophic signaling is a tangled web, as exemplified by leukemia inhibitory factor, which not only promotes hypertrophy via JAK/STAT but also operates through calcium-dependent signaling involving calmodulin-dependent protein kinases and calcineurin.80 These calcium-activated signaling molecules mediate powerful hypertrophic responses and represent well-studied examples of the necessary homeostatic balance required to maintain cardiac structure and function.
Calcium-Dependent Signaling
Fundamental hemodynamic reciprocity dictates that rising mechanical stress must be countered with increased cardiac contractility. This involves changes in calcium transients. Increases in calcium can involve a variety of mechanisms including stretch-activated channels and L-type calcium channels,81 synthesis and secretion of natriuretic peptides,82,83 activation of heat shock factor,84 and modulation of cell volume.85 As the mechanotransduction response gathers momentum, combinatorial pathways converge to elevate intracellular calcium levels. Synthesis of vasoactive peptide hormones such as angiotensin II and endothelin-1 prompted by mechanical stretch spread the message as paracrine and autocrine factors to promote calcium release.86 Endothelin-1 stimulates phospholipase C activity, generating inositol triphosphate and diacylglycerol, two agonists that elevate cytoplasmic free calcium levels.86–89 Angiotensin II increases intracellular calcium by altering L-type calcium channel conductance and producing capacitive calcium entry, a process wherein depletion of sarcoplasmic reticulum calcium stores elicits a sustained rise in cytosolic calcium dependent on extracellular calcium influx.90
In addition to the functional impact of increasing contractility, increasing intracellular calcium levels also activate molecular signaling that ultimately can result in transcriptional reprogramming and structural remodeling. Prolonged calcium-dependent signaling leads to hypertrophy with characteristic changes in cell size, protein synthesis, myocardial mass, and hemodynamic performance. Calcium-activated signaling and the concomitant recruitment of hypertrophic pathways are a critical driving force for the structural remodeling that characterizes hypertrophy. Cardiomyocytes decipher the ambient cytosolic calcium level using calmodulin that, when bound to calcium, triggers the activation of hypertrophic signaling. Calmodulin overexpression induces pathological hypertrophy in vivo,91 and calmodulin antagonist can block hypertrophy of cultured cardiomyocytes.92 Calmodulin directs hypertrophy through downstream target molecules such as Ca2+/calmodulin-dependent protein kinase (CaMK) and calcineurin.
The CaMK family consists of multiple members that seem rather promiscuous in substrate preference, phosphorylating a variety of critical functional molecules that regulate calcium levels, contractility, and transcription.93 Not surprisingly, the expression of activated CaMK induces hypertrophic changes both in vitro and in vivo. Cardiac-restricted expression of CaMK leads to involvement of phosphatase molecules that form complexes with CaMK and are likely to be contributory participants in furthering hypertrophy.94 Thus, phosphatases represent another branch of Ca2+/calmodulin-dependent signaling integrated with hypertrophic signaling.
Among cardiac phosphatases, calcineurin is the most extensively characterized hypertrophic signaling molecule. Like CaMK, calcineurin is activated by Ca2+/calmodulin-dependent signaling, and cardiac-specific overexpression leads to pathological hypertrophic remodeling.95 Although the ability to blunt hypertrophic remodeling by inhibition of calcineurin was initially controversial,96 a preponderance of published evidence indicates that calcineurin is activated by a wide range of stimuli and that inhibition of calcineurin blunts hypertrophic remodeling.97 In the context of calcineurin-driven hypertrophy, the phosphorylation state of nuclear factor of activated T cells (NFAT) is the key. Dephosphorylated NFAT accumulates in the nucleus and mediates transcriptional reprogramming, leading to hypertrophy.98 Nuclear accumulation of NFAT is countered by the action of glycogen synthase kinase 3ß, which phosphorylates NFAT, thereby increasing nuclear exit of the transcription factor and antagonizing hypertrophic reprogramming.99
Additional facets of calcium-dependent signaling in response to mechanical stretch include pathways radiating from pyk2/RAFTK as well as protein kinase C activation. Activation of pyk2/RAFTK, a calcium-activated tyrosine kinase related to focal adhesion kinase (FAK), occurs in response to elevation of intracellular calcium level in cardiomyocytes or hypertrophic stimulation100 and mechanical stress induced by pressure overload.101 The activation of pyk2/RAFTK that accompanies cardiac remodeling phosphorylates the adaptor protein paxillin that is a structural component of focal adhesions.102
Unlike the involvement of pyk2/RAFTK signaling in hypertrophic remodeling that is only now beginning to be examined, more than a decade has passed since initial observations that implicated protein kinase C activation in stretch-induced hypertrophy.103 Phospholipase activation in response to mechanical stretch or hypertrophic agonists was reported more than a decade ago.104 Phospholipase activation has been implicated in maladaptive signaling leading to heart failure105 as well as apoptosis in cultured cardiomyocytes,106 but the consequences of phospholipase activation are probably determined by multipath signaling interactions, because elevation of phospholipase was temporally disconnected from remodeling in vivo.107 The subsequent generation of diacylglycerol activates members of the protein kinase C family that mediate hypertrophic remodeling.108,109 More recently, elevation of calcium levels associated with activation of protein kinase C was found to precede development of cardiac hypertrophy.110 Protein kinase C expression induces hypertrophic remodeling through inextricable connections to the MAPK cascade that foster hypertrophic reprogramming111 as well as apoptosis.112
The Cytoskeleton
The membrane cytoskeleton is a critical junction for signal transduction in cardiomyocytes. The arrangement of the cytoskeleton is perhaps analogous to the ECM insofar as there are a variety of structural and soluble components that are essential for maintenance of cell structure and function. At this interface between cell and extracellular environment, signals are transduced, attachments to matrix proteins are established, and maintenance of cellular shape and structure is preserved. The cytoskeleton similarly provides an intracellular structure for transmitting contractile forces out of the cell to the matrix as well as a pathway for transmitting external forces into the cell and the nucleus and for distributing intracellular loads.
Accumulating experimental and clinical findings show association of cytoskeletal gene mutations with dilated cardiomyopathy.113 The diversity of these mutations (involving components of the sarcomeric cytoskeleton [titin], the sarcolemmal cytoskeleton [eg, , ß, and 
-sarcoglycan114], the z-disk [eg, muscle LIM protein115], intercalated disks [vinculin116], and the intermediate filament system [desmin117,118]) has led to the hypothesis that heart failure may be caused in this setting by an impairment of inside-out or outside-in mechanical signaling, although distinguishing these mechanisms is inherently difficult. This, in turn, would also suggest that similar mechanisms may be involved in acquired forms of heart disease triggered by altered mechanical loading of the heart.
A related possibility is the transmission of stretch-induced changes to alter transcriptional activity by direct coupling of cytoskeletal elements to chromatin or by nuclear trafficking of cytoskeletal protein. The former possibility was hypothesized for intermediate filaments of cardiomyocytes, which form a desmin-lamin network associated with nuclear envelope chromatin that could act to transmit altered forces.119 In the latter case, muscle LIM protein normally associated with the cytoskeleton120 accumulated in the nucleus after pressure overload.121 Whether this redistribution is causal or an epiphenomenon remains unclear, but direct communication between the cytoskeleton and the nucleus remains a tantalizing possibility to explain transcriptional reprogramming in response to stretch.
Cytoskeletal reorganization is a characteristic response of many cell types to fluid shear stress or stretch in vitro.122,123 Regulation of cytoskeletal structure in many cell types depends on Rho family small GTP-binding proteins that are stimulated through G protein—coupled receptors responsive to agonists released in response to stretch such as endothelin-1, phenylephrine, or angiotensin II.124 Two family members in particular, rhoA and rac1, are involved in hypertrophic remodeling,125–128 although both proteins originally achieved notoriety as regulatory switches controlling actin cytoskeletal organization in fibroblasts. Cytoskeletal reorganization is intrinsic to hypertrophic remodeling, so rhoA and rac1 are likely candidates to promote cytoskeletal assembly as well as activate kinases that are implicated in hypertrophic remodeling.129,130
The signaling hot spot for the cytoskeleton is the focal adhesion complex: a multimolecular structure consisting of structural proteins, signaling molecules, and transmembrane receptors. Focal adhesions are dynamic structures that respond to mechanical stress with rapid reorganization and formation.131,132 Integrins play a critical role in directing the assembly of adhesion complexes133,134 as well as stimulating hypertrophic signaling in response to mechanical stress.135 Integrin engagement may serve as the stimulus for cytoskeletal remodeling in response to mechanical strain induced by pressure overload in vivo.133 Upon stimulation, bidirectional multicomponent signaling converges on the focal adhesion complex involving kinases as well as adapter proteins that serve as docking sites for recruitment of additional molecules.135 Among these molecular participants, FAK is the best characterized member of the cytoskeletal signaling cascade in cardiomyocytes. FAK activation in response to signals provided by the extracellular matrix as well as hypertrophic agonists promotes remodeling.136 The hypertrophic action of FAK depends, in part, upon association with p130Cas, an adaptor protein localized in adhesion complexes.137 Additional kinases recruited into the signaling response to stretch include src and phosphoinositide 3-kinase (PI3-K).138 Involvement of kinases such as PI3-K and FAK in response to mechanical stretch points toward another signaling intersection where cytoskeletal remodeling and cell survival meet. Inhibition of FAK activity in cultured cardiomyocytes leads to loss of adhesion complex structure ultimately ending in cell death by anoikis,139 indicating the impact of FAK activity on multiple facets of cell structure and function. Whether this process of cell suicide by detachment occurs in the context of heart failure is an emerging issue in ongoing studies of myocardial apoptosis.
Survival
Although the hypertrophic response to stretch is often considered primarily in the context of structural remodeling, activation of survival pathways is equally critical in the molecular compensatory response to stretch. Mechanical stress in the myocardium is an indication that homeostatic conditions have gone awry, and ensuing remodeling combines altered adhesion and elevation of intracellular calcium that could act as a prescription for programmed cardiomyocyte cell death.139,140 Activation of survival signaling counterbalances proapoptotic stimuli, impinging on the cardiomyocyte, and diminishes cell dropout during the remodeling process. Hypertrophic and survival signaling often go hand-in-hand as exemplified by calcineurin141 and IGF-1142 (which may be linked143), TNF-,144 cardiotrophin 1,145,146 and MAPK.147,148 However, antiapoptotic activities are highly context-dependent and some of these same effectors are capable of contributing to apoptosis under different conditions.149
A recurring theme in survival signaling for many hypertrophic cascades involves the PI3-K/Akt pathway. Akt, well known as an antiapoptotic kinase in cardiomyocytes,150 induces hypertrophic remodeling in vitro and in vivo when overexpressed in a constitutively activated form.151,152 Elevated mechanical stress induced by pressure overload activates the PI3-K/Akt signaling pathway,153 perhaps mediated through FAK association with the p85 PI3-K subunit.154 Modulation of Akt by integrins suggests that matrix-derived mechanical stimulation may be a factor in activity,155,156 although this possibility remains to be explored in the context of cardiomyocytes. PI3-K/Akt activity is also stimulated through part of the gp130 signaling cascade activated by the paracrine factor LIF.157,158 Akt is a rather promiscuous kinase, so localization may provide important clues regarding its mode of biological action. Localization of activated Akt in cardiomyocytes suggests that relevant target molecules are nuclear-related.159 For example, induction of hypoxia-inducible factor 1 (HIF-1), a cellular transcription factor that regulates VEGF synthesis, is driven by the Akt signaling pathway in response to stretch.160 Akt-mediated phosphorylation also inactivates glycogen synthase kinase 3ß, which exerts powerful antihypertrophic effects in cardiomyocytes.99,161 Also, a growing body of evidence indicates that Akt influences cardiac growth via activation of the mammalian target of rapamycin (mTOR).152,162 The actions of Akt are likely to influence and be influenced by concomitant signaling from other hypertrophic pathways.163 Despite our modest understanding of the mechanisms responsible for integrating these concurrent signals, it is clear that cardiac remodeling in response to mechanical stretch involves signals for cell survival as well as remodeling.
None of the Above: Additional Parallel and Intersecting Pathways
As if the preceding sections are not enough, there is even more. A few additional signals in response to mechanical stretch are featured in an online data supplement (see http://www.circresaha.org), without particular order and with apologies to anyone who feels his or her favorite mechanotransduction pathway has been slighted by omission. This supplemental section briefly highlights heat shock proteins, nuclear factor-
B (NF-B), iex-1, atrial natriuretic factor (ANF), and estrogen.
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Conclusions |
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Although much is known about the individual components of mechanical signaling, it is apparent that much is to be learned concerning the integration of these components. How the mechanical force generated by the contraction of myocytes and fibroblasts influences the organization of the ECM is not known but clearly is important, especially in response to hypertrophic growth as well as in remodeling. Abnormal accumulation and arrangement of the ECM in response to increased mechanical tension would likely lead to abnormal mechanical properties of the ECM and contribute to the overall altered efficiency of the heart. As details of biochemical signaling pathways governing myocardial hypertrophy and remodeling come into more complete focus, our understanding of how these mechanisms apply in vivo will require a corresponding detailed mapping of the physical interactions between the myofilaments, cytoskeleton, membrane, receptors, cell-cell junctions, and ECM components, and how changes in each component redistribute mechanical signals among the other elements of the network.
The cornucopia of mechanical signals impinging on a cardiomyocyte contains powerful activators of the hypertrophic program with profound consequences for myocardial structure and function. The abundance of crosstalk and synergism existing between hypertrophic signaling cascades remains elusive. Moreover, the true magic of adaptive signaling lies in understanding how these multiple bidirectional signals are interrelated into a controlled and balanced remodeling process. Blunted hypertrophic remodeling by selective inhibition of target molecules that seem overtly unrelated should serve as reminders that hypertrophy is an exquisitely integrated process involving numerous components, both critical and/or redundant in nature. Our sophisticated efforts to understand molecular signaling through surgical interventions, transgenesis, or gene deletion are relatively clumsy manipulations compared with the dynamic and subtle shifts in activity that occur in physiological responses. The paradoxical and aberrant effects observed in experimental model systems are likely due to alteration of normal homeostatic regulation resulting from overloading or eliminating a normal facet of the signaling cascade. And yet, these heavy-handed approaches have elucidated and immeasurably enhanced our understanding and appreciation for the complexity of hypertrophic remodeling. Because uncertainties remain regarding the adaptive value of this compensatory response,164 we must understand how the response to mechanical stress is initiated and controlled. And, as multiplex signaling relationships in the myocardium begin to emerge, the challenge will be to unravel how the myocardium interprets this barrage of information to direct an adaptive remodeling response. And yet, despite the complex orchestrated response of the myocardium, the long-term consequences of remodeling often lead the heart into failure. As functional performance of the stretched myocardium sinks, the accompanying song of signaling molecules, much like the dance band on the Titanic, plays on.
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Acknowledgments |
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M.A.S.’s research is funded by grants from the NIH (HL 58224, HL66035, and HL67245 and an Established Investigator Award from the American Heart Association). A.M. is funded by NIH grant PO1 HL46345. T.K.B. is funded by NIH grants HL 37669, HL59981, and HL68038. The authors thank Richard Hunt for his drawing skills and Edie Goldsmith for her editorial comments.
Received August 14, 2002; revision received September 27, 2002; accepted October 2, 2002.
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References |
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1. Ruwhof C, van der Laarse A. Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc Res. 2000; 47: 23–37.
2. Sadoshima J, Izumo S. The cellular and molecular response of cardiac myocytes to mechanical stress. Annu Rev Physiol. 1997; 59: 551–571.[CrossRef][Medline] [Order article via Infotrieve]
3. Tavi P, Laine M, Weckstrom M, Ruskoaho H. Cardiac mechanotransduction: from sensing to disease and treatment. Trends Pharmacol Sci. 2001; 22: 254–260.[CrossRef][Medline] [Order article via Infotrieve]
4. Adams JC. Cell-matrix contact structures. Cell Mol Life Sci. 2001; 58: 371–392.[CrossRef][Medline] [Order article via Infotrieve]
5. Bornstein P. Matricellular proteins: an overview. Matrix Biol. 2000; 19: 555–556.[CrossRef][Medline] [Order article via Infotrieve]
6. Holmgren E. Uber die trophospongien der quergestreiften muskelfasern, nebst bemerkungen uber den allgemeinen bau dieser fasern. Arch Mikrosk Anat. 1907; 71: 165–178.[CrossRef]
7. Nagel A. Die mechanischen ergenschoften der kapillarwand und ihre beziehungen zum bindegewebslager. Z Zellforsch Mikrosk Anat. 1934; 21: 376–387.[CrossRef]
8. Borg TK, Caulfield JB. The collagen matrix of the heart. Fed Proc. 1981; 40: 2037–2041.[Medline] [Order article via Infotrieve]
9. Cheng YS, Champliaud MF, Burgeson RE, Marinkovich MP, Yurchenco PD. Self assembly of laminin isoforms. J Biol Chem. 1997; 272: 31525–31532.
10. Granzier HL, Irving TC. Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. Biophys J. 1995; 68: 1027–1044.[Medline] [Order article via Infotrieve]
11. Granzier H, Labeit S. Cardiac titin: an adjustable multi-functional spring. J Physiol (Lond). 2002; 541: 335–342.
12. MacKenna DA, Vaplon SM, McCulloch AD. Microstructural model of perimysial collagen fibers for resting myocardial mechanics during ventricular filling. Am J Physiol. 1997; 273: H1576–H1586.[Medline] [Order article via Infotrieve]
13. MacKenna DA, Omens JH, Covell JW. Left ventricular perimysial collagen fibers uncoil rather than stretch during diastolic filling. Basic Res Cardiol. 1996; 91: 111–112.[CrossRef][Medline] [Order article via Infotrieve]
14. de Tombe PP, ter Keurs HE. An internal viscous element limits unloaded velocity of sarcomere shortening in rat myocardium. J Physiol (Lond). 1992; 454: 619–642.
15. Borg TK, Ranson WF, Moslehy FA, Caulfield JB. Structural basis of ventricular stiffness. Lab Invest. 1981; 44: 49–54.[Medline] [Order article via Infotrieve]
16. Burlew BS, Weber KT. Cardiac fibrosis as a cause of diastolic dysfunction. Herz. 2002; 27: 92–98.[CrossRef][Medline] [Order article via Infotrieve]
17. LeGrice IJ, Takayama Y, Covell JW. Transverse shear along myocardial cleavage planes provides a mechanism for normal systolic wall thickening. Circ Res. 1995; 77: 182–193.
18. Costa KD, Takayama Y, McCulloch AD, Covell JW. Laminar fiber architecture and three-dimensional systolic mechanics in canine ventricular myocardium. Am J Physiol. 1999; 276(2 pt 2): H595–H607.
19. Schoenberg M. Geometrical factors influencing muscle force development, II: radial forces. Biophys J. 1980; 30: 69–77.[Medline] [Order article via Infotrieve]
20. Lin DHS, Yin FCP. A multiaxial constitutive law for mammalian left ventricular myocardium in steady-state barium contracture or tetanus. J Biomech Eng. 1998; 120: 504–517.[Medline] [Order article via Infotrieve]
21. Takayama Y, Costa KD, Covell JW. Contribution of laminar myofiber architecture to load-dependent changes in mechanics of LV myocardium. Am J Physiol Heart Circ Physiol. 2002; 282: H1510–H1520.
22. Usyk TP, Mazhari R, McCulloch AD. Effect of laminar orthotropic myofiber architecture on regional stress and strain in the canine left ventricle. J Elast. 2000; 61: 143–164.[CrossRef]
23. Konhilas JP, Irving TC, de Tombe PP. Myofilament calcium sensitivity in skinned rat cardiac trabeculae: role of interfilament spacing. Circ Res. 2002; 90: 59–65.
24. Wang N, Butler JP, Ingber DE. Mechanotransduction across the cell surface and through the cytoskeleton. Science. 1993; 260: 1124–1127.
25. Simpson DG, Majeski M, Borg TK, Terracio L. Regulation of cardiac myocyte protein turnover and myofibrillar structure in vitro by specific directions of stretch. Circ Res. 1999; 85: e59–e69.[Medline] [Order article via Infotrieve]
26. Gopalan SM, Flaim C, Bhatia SN, Hoshijima M, Knoell R, Chien KR, et al. Anisotropic stretch-induced hypertrophy in neonatal ventricular myocytes micropatterned on deformable elastomers. Biotechnol Bioeng. In press.
27. Omens JH, Fung YC. Residual strain in rat left ventricle. Circ Res. 1990; 66: 37–45.
28. MacKenna DA, Omens JH, McCulloch AD, Covell JW. Contribution of the endomysial collagen matrix to passive left ventricular mechanics in the isolated rat heart. Am J Physiol. 1994; 266: H1007–H1018.[Medline] [Order article via Infotrieve]
29. Rodriguez EK, Omens JH, Waldman LK, McCulloch AD. Effect of residual stress on transmural sarcomere length distribution in rat left ventricle. Am J Physiol. 1993; 264: H1048–H1056.[Medline] [Order article via Infotrieve]
30. Guccione JM, McCulloch AD, Waldman LK. Passive material properties of intact ventricular myocardium determined from a cylindrical model. J Biomech Eng. 1991; 113: 42–55.[Medline] [Order article via Infotrieve]
31. Omens JH, Rockman HA, Covell JW. Passive ventricular mechanics in tight-skin mice. Am J Physiol. 1994; 266: H1169–H1176.[Medline] [Order article via Infotrieve]
32. Weis SM, Emery JL, Becker D, McBride DJ, Omens JH, McCulloch AD. Myocardial mechanics and collagen structure in the osteogenesis imperfecta murine. Circ Res. 2000; 87: 663–669.
33. LeGrice IJ, Smaill BH, Chai LZ, Edgar SG, Gavin JB, Hunter PJ. Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog. Am J Physiol. 1995; 269(2 pt 2): H571–H582.
34. Sedmera D, Pexieder T, Hu N, Clark EB. Developmental changes in the myocardial architecture of the chick. Anat Rec. 1997; 248: 421–432.[CrossRef][Medline] [Order article via Infotrieve]
35. Obrink B. A study of the interactions between monomeric tropocollagen and glycosaminoglycans. Eur J Biochem. 1973; 33: 387–400.[Medline] [Order article via Infotrieve]
36. Reed RK, Rubin K, eds. Connective Tissue Biology, Integration, and Reductionism. London, UK: Portland Press; 1998. Wenner-Gren International Series; vol 71.
37. Ehrlich HP, Gabbiani G, Meda P. Cell coupling modulates the contraction of fibroblast-populated collagen lattices. J Cell Physiol. 2000; 184: 86–92.[CrossRef][Medline] [Order article via Infotrieve]
38. Grinnell F. Fibroblast-collagen matrix contraction: growth factor signaling and mechanical loading. Trends Cell Biol. 2000; 10: 362–365.[CrossRef][Medline] [Order article via Infotrieve]
39. Cukierman E, Pankov R, Stevens DR, Yamada KM. Taking cell-matrix adhesions to the third dimension. Science. 2001; 294: 1661–1663.
40. Ivarsson M, McWhirter A, Borg TK, Rubin K. Type I collagen synthesis in cultured human fibroblasts: regulation by cell spreading, platelet derived growth factor and interactions with collagen fibers. Matrix Biol. 1998; 16: 409–425.[CrossRef][Medline] [Order article via Infotrieve]
41. Schnee JM, Hsueh WA. Angiotensin II, adhesion, and cardiac fibrosis. Cardiovasc Res. 2000; 46: 264–268.
42. DeAlmeida A, Mustin D, Forman M, Brower G, Janicki JS, Carver W. Effects of mast cells on the behavior of isolated heart fibroblasts: modulation of collagen remodeling and gene expression. J Cell Physiol. 2002; 191: 51–59.[CrossRef][Medline] [Order article via Infotrieve]
43. Zimmerman SD, Karlon WJ, Holmes JW, Omens JH, Covell JW. Structural and mechanical factors influencing infarct scar collagen organization. Am J Physiol. 2000; 278: H194–H200.
44. Kohl P, Noble D. Mechanosensitive connective tissue: potential influence on heart rhythm. Cardiovasc Res. 1996; 32: 62–68.[CrossRef][Medline] [Order article via Infotrieve]
45. Prajapati RT, Chavally-Mis B, Hearbage D, Eastwood M, Brown RA. Mechanical loading regulates protease production by fibroblasts in three dimensional collagen substrates. Wound Rep Reg. 2000; 8: 226–237.[CrossRef][Medline] [Order article via Infotrieve]
46. Tyagi SC, Lewis K, Pikes D, Marcello A, Mujumdar FS, Simley LM, Moore CK. Stretch-induced membrane type matrix metalloproteinase and tissue plasminogen activator in cardiac fibroblast cells. J Cell Physiol. 1998; 176: 374–382.[CrossRef][Medline] [Order article via Infotrieve]
47. Ogawa E, Saito Y, Harada M, Kamitani S, Kuwahara K, Miyamoto Y, Ishikawa M, Hamanaka I, Kajiyama N, Takahashi N, Nakagawa O, Masuda I, Kishimoto I, Nakao K. Outside-in signaling of fibronectin stimulates cardiomyocyte hypertrophy in cultured neonatal rat ventricular myocytes. J Mol Cell Cardiol. 2000; 32: 765–776.[CrossRef][Medline] [Order article via Infotrieve]
48. Bouvard D, Brakebusch C, Gustafsson E, Aszódi A, Bengtsson T, Berna A, Fässler R. Functional consequences of integrin gene mutations in mice. Circ Res. 2001; 89: 211–223.
49. Giancotti FG, Ruoslahti E. Integrin signaling. Science. 1999; 285: 1028–1032.
50. Ross RS, Borg TK. Integrins and the myocardium. Circ Res. 2001; 88: 1112–1119.
51. Terracio L, Rubin K, Jyring R, Gullberg D, Carver W, Borg TK. Expression of collagen binding integrins during cardiac development and hypertrophy. Circ Res. 1991; 68: 734–744.
52. Shai SY, Harpf AE, Babbitt CJ, Jordan MC, Fishbein MC, Chjen J, Omura M, Leil TA, Becker KD, Jiang M, Smith DJ, Cherry SR, Loftus JC, Ross RS. Cardiac myocyte-specific excision of the ß1 integrin gene results in myocardial fibrosis and cardiac failure. Circ Res. 2002; 90: 458–464.
53. Vogel WF. Collagen receptor signaling in health and disease. Eur J Dermatol. 2001; 11: 506–514.[Medline] [Order article via Infotrieve]
54. Gumbiner BM. Regulation of cadherin adhesive activity. J Cell Biol. 2000; 148: 399–403.
55. MacKenna D, Summerour SR, Villarreal FJ. Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis. Cardiovasc Res. 2000; 46: 257–263.
56. Harada M, Saito Y, Kuwahara K, Ogawa E, Ishikawa M, Nakagawa O, Miyamoto Y, Kamitani S, Hamanaka I, Kajiyama N, Takahashi N, Masuda I, Itoh H, Nakao K. Interaction of myocytes and nonmyocytes is necessary for mechanical stretch to induce ANP/BNP production in cardiocyte culture. J Cardiovasc Pharmacol. 1998; 31 (suppl 1): S357–S359.[CrossRef][Medline] [Order article via Infotrieve]
57. Malhotra R, Sadoshima J, Brosius FC 3rd, Izumo S. Mechanical stretch and angiotensin II differentially upregulate the renin-angiotensin system in cardiac myocytes in vitro. Circ Res. 1999; 85: 137–146.
58. Simpson DG, Sharp WW, Borg TK, Price RL, Terracio L, Samarel AM. Mechanical regulation of cardiac myocyte protein turnover and myofibrillar structure. Am J Physiol. 1996; 270(4 pt 1): C1075–C1087.
59. Summerour SR, Villarreal FJ, McCulloch AD. Mechanical regulation of extracellular signal-regulated kinase and fibronectin transcriptional activity in adult rat cardiac fibroblasts. J Histochem Cytochem. 1999; 47: 1649. Abstract.
60. Lee AA, Delhaas T, McCulloch AD, Villarreal FJ. Differential responses of adult cardiac fibroblasts to in vitro biaxial strain patterns. J Mol Cell Cardiol. 1999; 31: 1833–1843.[CrossRef][Medline] [Order article via Infotrieve]
61. MacKenna DA, Dolfi F, Vuori K, Ruoslahti E. Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activation by mechanical stretch is integrin-dependent and matrix-specific in rat cardiac fibroblasts. J Clin Invest. 1998; 101: 301–310.[Medline] [Order article via Infotrieve]
62. van Wamel AJ, Ruwhof C, van der Valk-Kokshoom LE, Schrier PI, van der Laarse A. The role of angiotensin II, endothelin-1 and transforming growth factor-ß as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy. Mol Cell Biochem. 2001; 218: 113–124.[CrossRef][Medline] [Order article via Infotrieve]
63. Yamazaki T, Komuro I, Yazaki Y. Molecular aspects of mechanical stress-induced cardiac hypertrophy. Mol Cell Biochem. 1996; 163–164:197–201.
64. Li J, Hampton T, Morgan JP, Simons M. Stretch-induced VEGF expression in the heart. J Clin Invest. 1997; 100: 18–24.[Medline] [Order article via Infotrieve]
65. van Wamel AJ, Ruwhof C, van der Valk-Kokshoorn LJ, Schrier PI, van der Laarse A. Rapid effects of stretched myocardial and vascular cells on gene expression of neonatal rat cardiomyocytes with emphasis on autocrine and paracrine mechanisms. Arch Biochem Biophys. 2000; 381: 67–73.[CrossRef][Medline] [Order article via Infotrieve]
66. Russell FD, Molenaar P. The human heart endothelin system: ET-1 synthesis, storage, release, and effect. Trends Pharmacol Sci. 2000; 21: 353–359.[CrossRef][Medline] [Order article via Infotrieve]
67. Dostal DE, Baker KM. The cardiac renin-angiotensin system: conceptual or a regulator of cardiac function. Circ Res. 1999; 85: 643–650.
68. Clerk A, Sugden PH. Activation of protein kinase cascades in the heart by hypertrophic G protein-coupled receptor agonists. Am J Cardiol. 1999; 83: 64H–69H.[Medline] [Order article via Infotrieve]
69. Sugden PH. Signalling pathways in cardiac myocyte hypertrophy. Ann Med. 2001; 33: 611–622.[Medline] [Order article via Infotrieve]
70. Aikawa R, Nagai T, Kudoh S, Zou Y, Tanaka M, Tamura M, Akazawa H, Takano H, Nagai R, Komuro I. Integrins play a critical role in mechanical stress-induced p38 MAPK activation. Hypertension. 2002; 39: 233–238.
71. Kudoh S, Komuro I, Hiroi Y, Zou Y, Harada K, Sugaya T, Takekoshi N, Murakami K, Kadowaki T, Yazaki Y. Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin II type 1a receptor knockout mice. J Biol Chem. 1998; 273: 24037–24043.
72. Harada K, Komuro I, Zou Y, Kudoh S, Kijima K, Matsubara H, Sugaya T, Murakami K, Yazaki Y. Acute pressure overload could induce hypertrophic responses in the heart of angiotensin II type 1a knockout mice. Circ Res. 1998; 82: 779–785.
73. Kodama H, Fukuda K, Pan J, Makino S, Baba A, Hori S, Ogawa S. Leukemia inhibitory factor, a potent cardiac hypertrophic cytokine, activates the JAK/STAT pathway in rat cardiomyocytes. Circ Res. 1997; 81: 656–663.
74. Kunisada K, Tone E, Fujio Y, Matsui H, Yamauchi-Takihara K, Kishimoto T. Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes. Circulation. 1998; 98: 346–352.
75. Pan J, Fukuda K, Kodama H, Sano M, Takahashi T, Makino S, Kato T, Manabe T, Hori S, Ogawa S. Involvement of gp130-mediated signaling in pressure overload-induced activation of the JAK/STAT pathway in rodent heart. Heart Vessels. 1998; 13: 199–208.[CrossRef][Medline] [Order article via Infotrieve]
76. Pan J, Fukuda K, Saito M, Matsuzaki J, Kodama H, Sano M, Takahashi T, Kato T, Ogawa S. Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. Circ Res. 1999; 84: 1127–1136.
77. Hirota H, Chen J, Betz UA, Rajewsky K, Gu Y, Ross J Jr, Muller W, Chien KR. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell. 1999; 97: 189–198.[CrossRef][Medline] [Order article via Infotrieve]
78. Yamauchi-Takihara K, Kishimoto T. A novel role for STAT3 in cardiac remodeling. Trends Cardiovasc Med. 2000; 10: 298–303.[CrossRef][Medline] [Order article via Infotrieve]
79. Yasukawa H, Hoshijima M, Gu Y, Nakamura T, Pradervand S, Hanada T, Hanakawa Y, Yoshimura A, Ross J Jr, Chien KR. Suppressor of cytokine signaling-3 is a biomechanical stress-inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways. J Clin Invest. 2001; 108: 1459–1467.[CrossRef][Medline] [Order article via Infotrieve]
80. Kato T, Sano M, Miyoshi S, Sato T, Hakuno D, Ishida H, Kinoshita-Nakazawa H, Fukuda K, Ogawa S. Calmodulin kinases II and IV and calcineurin are involved in leukemia inhibitory factor-induced cardiac hypertrophy in rats. Circ Res. 2000; 87: 937–945.
81. Ruwhof C, van Wamel JT, Noordzij LA, Aydin S, Harper JC, van der Laarse A. Mechanical stress stimulates phospholipase C activity and intracellular calcium ion levels in neonatal rat cardiomyocytes. Cell Calcium. 2001; 29: 73–83.[CrossRef][Medline] [Order article via Infotrieve]
82. Calaghan SC, White E. The role of calcium in the response of cardiac muscle to stretch. Prog Biophys Mol Biol. 1999; 71: 59–90.[CrossRef][Medline] [Order article via Infotrieve]
83. Laine M, Id L, Vuolteenaho O, Ruskoaho H, Weckstrom M. Role of calcium in stretch-induced release and mRNA synthesis of natriuretic peptides in isolated rat atrium. Pflugers Arch. 1996; 432: 953–960.[CrossRef][Medline] [Order article via Infotrieve]
84. Chiang J, Wasser JS, Cornelussen RNM, Knowlton AA. Activation of heat shock factor by stretch-activated channels in rat hearts. Circulation. 2001; 104: 209–214.
85. Suleymanian MA, Clemo HF, Cohen NM, Baumgarten CM. Stretch activated channel blockers modulate cell volume in cardiac ventricular myocytes. J Mol Cell Cardiol. 1995; 27: 721–728.[Medline] [Order article via Infotrieve]
86. Lipp P, Laine M, Tovey SC, Burrell KM, Berridge MJ, Li W, Bootman MD. Functional InsP3 receptors that may modulate excitation-contraction coupling in the heart. Curr Biol. 2000; 10: 939–941.[CrossRef][Medline] [Order article via Infotrieve]
87. Liu SJ, Kennedy RH. 1-Adrenergic activation of L-type calcium current in rat ventricular myocytes: perforated patch clamp recordings. Am J Physiol. 1998; 274: H2203–H2207.[Medline]
[Order article via Infotrieve]
88. Petroff MG, Aiello EA, Palomeque J, Salas MA, Mattiazzi A. Subcellular mechanisms of the positive inotropic effect of angiotensin II in cat myocardium. J Physiol. 2000; 529: 189–203.
89. Petroff MG, Kim SH, Pepe S, Dessy C, Marban E, Balligand JL, Sollott SJ. Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nat Cell Biol. 2001; 3: 867–873.[CrossRef][Medline] [Order article via Infotrieve]
90. Hunton DL, Lucchesi PA, Pang Y, Cheng X, Dell’Italia LJ, Marchase RB. Capacitative calcium entry contributes to nuclear factor of activated T cells nuclear translocation and hypertrophy in cardiomyocytes. J Biol Chem. 2002; 277: 14266–14273.
91. Gruver CL, DeMayo F, Goldstein MA, Means AR. Targeted developmental overexpression of calmodulin induces proliferative and hypertrophic growth of cardiomyocytes in transgenic mice. Endocrinology. 1993; 133: 376–388.
92. McDonough PM, Glembotski CC. Induction of atrial natriuretic factor and myosin light chain-2 gene expression in cultured ventricular myocytes by electrical stimulation of contraction. J Biol Chem. 1992; 267: 11665–11668.
93. Braun AP, Schuman H. The multifunctional calcium/calmodulin-dependent protein kinase: from form to function. Annu Rev Physiol. 1995; 57: 417–445.[CrossRef][Medline] [Order article via Infotrieve]
94. Zhang T, Johnson EN, Gu Y, Morissette MR, Sah VP, Gigena MS, Belke DD, Dillmann WH, Rogers TB, Schuman H, Ross J Jr, Brown JH. The cardiac-specific nuclear B isoform of Ca2+/calmodulin-dependent protein kinase II induces hypertrophy and dilated cardiomyopathy associated with increased protein phosphatase 2a activity. J Biol Chem. 2002; 277: 1261–1267.
95. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998; 93: 215–228.[CrossRef][Medline] [Order article via Infotrieve]
96. Sugden PH. Signaling in myocardial hypertrophy: life after calcineurin? Circ Res. 1999; 84: 633–646.
97. Wilkins BJ, Molkentin JD. Calcineurin and cardiac hypertrophy: where have we been? Where are we going? J Physiol. 2002; 541: 1–8.
98. Antos CL, McKinsey TA, Frey N, Kutschke W, McAnally J, Shelton JM, Richardson JA, Hill JA, Olson EN. Activated glycogen synthase kinase-3ß suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A. 2002; 99: 907–912.
99. Hardt SE, Sadoshima J. Glycogen synthase kinase-3ß: a novel regulator of cardiac hypertrophy and development. Circ Res. 2002; 90: 1055–1063.
100. Bayer AL, Ferguson AG, Lucchesi PA, Samarel AM. Pyk2 expression and phosphorylation in neonatal and adult cardiomyocytes. J Mol Cell Cardiol. 2001; 33: 1017–1030.[CrossRef][Medline] [Order article via Infotrieve]
101. Bayer AL, Heidkamp MC, Patel N, Porter MJ, Engman SJ, Samarel AM. PYK2 expression and phosphorylation increases in pressure overload-induced left ventricular hypertrophy. Am J Physiol. 2002; 283: H695–H706.
102. Melendez J, Gaines L, Welch S, Schaefer E, Moravec CS, Avraham S, Avraham H, Sussman MA. Activation of pyk2/RAFTK and FAK in cardiac remodeling. J Biol Chem. September 12, 2002; 10.1074/jbc.M204886200. Available at http://www.jbc.org. Accessed October 9, 2002.
103. Komuro I, Katoh Y, Kaida T, Shibazaki Y, Kurabayashi M, Hoh E, Takaku F, Yazaki Y. Mechanical loading stimulates cell hypertrophy and specific gene expression in cultured rat cardiac myocytes: possible role of protein kinase C activation. J Biol Chem. 1991; 266: 1265–1268.
104. Sadoshima J, Izumo S. Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J. 1993; 12: 1681–1692.[Medline] [Order article via Infotrieve]
105. Ju H, Zhao S, Tappia PS, Panagia V, Dixon IMC. Expression of Gq and PLC-ß in scar and border tissue in heart failure due to myocardial infarction. Circulation. 1998; 97: 892–899.
106. Adams JW, Pagel AL, Means CK, Oksenberg D, Armstrong RC, Brown JH. Cardiomyocyte apoptosis induced by Gq signaling is mediated by permeability transition pore formation and activation of the mitochondrial death pathway. Circ Res. 2000; 87: 1180–1187.
107. Mende U, Semsarian C, Martins DC, Kagen A, Duffy C, Schoen FJ, Neer EJ. Dilated cardiomyopathy in two transgenic mouse lines expressing activated G protein q: lack of correlation between phospholipase C activation and the phenotype. J Mol Cell Cardiol. 2001; 33: 1399–1403.[CrossRef][Medline]
[Order article via Infotrieve]
108. Muth JN, Bodi I, Lewis W, Varadi G, Schwartz A. A Ca2+-dependent transgenic model of cardiac hypertrophy: a role for protein kinase C. Circulation. 2001; 103: 140–147.
109. Strait JB 3rd, Martin JL, Bayer A, Mestril R, Eble DM, Samarel AM. Role of protein kinase C-
in hypertrophy of cultured neonatal rat ventricular myocytes. Am J Heart Circ Physiol. 2001; 280: H756–H766.
110. Bowman JC, Steinberg SF, Jiang T, Geenen DL, Fishman GI, Buttrick PM. Expression of protein kinase Cß in the heart causes hypertrophy in adult mice and sudden death in neonates. J Clin Invest. 1997; 81: 1027–1033.
111. Braz JC, Bueno OF, De Windt LJ, Molkentin JD. PKC regulates the hypertrophic growth of cardiomyocytes through extracellular signal-regulated kinase 1/2 (ERK 1/2). J Cell Biol. 2002; 156: 905–919.
112. Shizukuda Y, Buttrick PM. Protein kinase C() modulates apoptosis induced by ß-adrenergic stimulation in adult rat ventricular myocytes via extracellular signal-regulated kinase (ERK) activity. J Mol Cell Cardiol. 2001; 33: 1791–1803.[CrossRef][Medline]
[Order article via Infotrieve]
113. Hosino T, Fujiwara H, Kawai C, Hamashima Y. Myocardial fiber diameter and regional distribution in the ventricular wall of normal adult hearts, hypertensive hearts and hearts with hypertrophic cardiomyopathy. Circulation. 1983; 67: 1109–1116.
114. Durbeej M, Campbell KP. Muscular dystrophies involving the dystrophin-glycoprotein complex: an overview of current mouse models. Curr Opin Genet Dev. 2002; 12: 349–361.[CrossRef][Medline] [Order article via Infotrieve]
115. Arber S, Hunter JJ, Ross J Jr, Hongo M, Sansig G, Borg J, Perriard JC, Chien KR, Caroni P. MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell. 1997; 88: 393–403.[CrossRef][Medline] [Order article via Infotrieve]
116. Olson TM, Illenberger S, Kishimoto NY, Huttelmaier S, Keating MT, Jockusch BM. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation. 2002; 105: 431–437.
117. Towbin JA, Bowles NE. Molecular genetics of left ventricular dysfunction. Curr Mol Med. 2001; 1: 81–90.[CrossRef][Medline] [Order article via Infotrieve]
118. Carlsson L, Thornell LE. Desmin-related myopathies in mice and man. Acta Physiol Scand. 2001; 171: 341–348.[CrossRef][Medline] [Order article via Infotrieve]
119. Bloom S, Lockhard VG, Bloom M. Intermediate filament-mediated stretch-induced changes in chromatin: a hypothesis for growth initiation in cardiac myocytes. J Mol Cell Cardiol. 1996; 28: 2123–2127.[CrossRef][Medline] [Order article via Infotrieve]
120. Flick MJ, Konieczny SF. The muscle regulatory and structural protein MLP is a cytoskeletal binding partner of ßI-spectrin. J Cell Sci. 2000; 113: 1553–1564.[Abstract]
121. Ecarnot-Laubriet A, De Luca K, Vandroux D, Moisant M, Bernard C, Assem M, Rochette L, Teyssier JR. Downregulation and nuclear relocation of MLP during the progression of right ventricular hypertrophy induced by chronic pressure overload. J Mol Cell Cardiol. 2000; 32: 2385–2395.[CrossRef][Medline] [Order article via Infotrieve]
122. Hayakawa K, Sato N, Obinata T. Dynamic reorientation of cultured cells and stress fibers under mechanical stress from periodic stretching. Exp Cell Res. 2001; 268: 104–114.[CrossRef][Medline] [Order article via Infotrieve]
123. Galbraith CG, Skalak R, Chien S. Shear stress induces spatial reorganization of the endothelial cell cytoskeleton. Cell Motil Cytoskeleton. 1998; 40: 317–330.[CrossRef][Medline] [Order article via Infotrieve]
124. Clerk A, Sugden PH. Small guanine nucleotide-binding proteins and myocardial hypertrophy. Circ Res. 2000; 86: 1019–1023.
125. Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Zhu W, Kadowaki T, Yazaki Y. Rho family small G proteins play critical roles in mechanical stress-induced hypertrophic responses in cardiac myocytes. Circ Res. 1999; 84: 458–466.
126. Hoshijima M, Sah VP, Wang Y, Chien KR, Brown JH. The low molecular weight GTPase Rho regulates myofibril formation and organization in neonatal rat cardiac myocytes: involvement of Rho kinase. J Biol Chem. 1998; 273: 7725–7730.
127. Pracyk JB, Tanaka K, Hegland DD, Kim KS, Sethi R, Rovira II, Blazina DR, Lee L, Bruder JT, Kovesdi I, Goldschmidt-Clermont PJ, Irani K, Finkel T. A requirement for the rac1 GTPase in the signal transduction pathway leading to cardiac myocyte hypertrophy. J Clin Invest. 1998; 102: 929–937.[Medline] [Order article via Infotrieve]
128. Sussman MA, Welch S, Walker A, Klevitsky R, Hewett TE, Price RL, Schaefer E, Yager K. Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1. J Clin Invest. 2000; 105: 875–886.[Medline] [Order article via Infotrieve]
129. Clerk A, Pham FH, Fuller SJ, Sahai E, Aktories K, Marais R, Marshall C, Sugden PH. Regulation of mitogen-activated protein kinases in cardiac myocytes through the small G protein Rac1. Mol Cell Biol. 2001; 21: 1173–1184.
130. Yanazume T, Hasegawa K, Wada H, Morimoto T, Abe M, Kawamura T, Sasayama S. Rho/ROCK pathway contributes to the activation of extracellular signal-regulated kinase/GATA-4 during myocardial cell hypertrophy. J Biol Chem. 2002; 277: 8618–8625.
131. Sharp WW, Simpson DG, Borg TK, Samarel AM, Terracio L. Mechanical forces regulate focal adhesion and costamere assembly in cardiac myocytes. Am J Physiol. 1997; 273: H546–H556.[Medline] [Order article via Infotrieve]
132. Goldmann WH. Mechanical aspects of cell shape regulation and signaling. Cell Biol Int. 2002; 26: 313–317.[CrossRef][Medline] [Order article via Infotrieve]
133. Laser M, Wiley CD, Jiang W, Cooper G 4th, Menick DR, Zile MR, Kuppuswamy D. Integrin activation and focal complex formation in cardiac hypertrophy. J Biol Chem. 2000; 275: 35624–35630.
134. Nagai T, Laser M, Baicu CF, Zile MR, Cooper G 4th, Kuppuswamy D. ß3-Integrin-mediated focal adhesion complex formation: adult cardiomyocytes embedded in three-dimensional polymer matrices. Am J Cardiol. 1999; 83: 38H–43H.[Medline] [Order article via Infotrieve]
135. Franchini KG, Torsoni AS, Soares PHA, Saad MJA. Early activation of the multicomponent signaling complex associated with focal adhesion kinase induced by pressure overload in the rat heart. Circ Res. 2000; 87: 558–565.
136. Taylor JM, Rovin JD, Parsons JT. A role for focal adhesion kinase in phenylephrine-induced hypertrophy of rat ventricular cardiomyocytes. J Biol Chem. 2000; 275: 19250–19257.
137. Kovacic-Milivojevic B, Roediger F, Almeida EAC, Damsky CH, Gardner DG, Ilic D. Focal adhesion kinase and p130Cas mediate both sarcomeric organization and activation of genes associated with cardiac and myocyte hypertrophy. Mol Biol Cell. 2001; 12: 2290–2307.
138. Domingos PP, Fonseca PM, Nadruz W Jr, Franchini KG. Load-induced focal adhesion kinase activation in the myocardium: role of stretch and contractile activity. Am J Physiol. 2002; 282: H556–H564.
139. Heidkamp MC, Bayer AL, Kalina JA, Eble DM, Samarel AM. GFP-FRNK disrupts focal adhesions and induces anoikis in neonatal rat ventricular myocytes. Circ Res. 2002; 90: 1282–1289.
140. Pacher P, Csordas G, Hajnoczky G. Mitochondrial Ca2+ signaling and cardiac apoptosis. Biol Signals Recept. 2001; 10: 200–223.[CrossRef][Medline] [Order article via Infotrieve]
141. De Windt LJ, Lim HW, Taigen T, Wencker D, Condorelli G, Dorn GW 2nd, Kitsis RN, Molkentin JD. Calcineurin-mediated hypertrophy protects cardiomyocytes from apoptosis in vitro and in vivo: an apoptosis independent-independent model of dilated heart failure. Circ Res. 2000; 86: 255–263.
142. Li Q, Li B, Wang X, Leri A, Jana KP, Liu Y, Kajstura J, Baserga R, Anversa P. Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J Clin Invest. 1997; 100: 1991–1999.[Medline] [Order article via Infotrieve]
143. Miyashita T, Takeishi Y, Takahashi H, Kato S, Kubota I, Tomoike H. Role of calcineurin in insulin-like growth factor-1-induced hypertrophy of cultured adult rat ventricular myocytes. Jpn Circ J. 2001; 65: 815–819.[CrossRef][Medline] [Order article via Infotrieve]
144. Kubota Y, Miyagishima M, Frye CS, Alber SM, Bounoutas GS, Kadokami T, Watkins SC, McTiernan CF, Feldman AM. Overexpression of tumor necrosis factor activates both anti- and pro-apoptotic pathways in the myocardium. J Mol Cell Cardiol. 2001; 33: 1331–1344.[CrossRef][Medline]
[Order article via Infotrieve]
145. Pennica D, King KL, Shaw KJ, Luis E, Rullamas J, Luoh SM, Darbonne WC, Knutzon DS, Yen R, Chien KR. Expression cloning of cardiotrophin 1, a cytokine that induces myocyte hypertrophy. Proc Natl Acad Sci U S A. 1995; 92: 1142–1146.
146. Sheng Z, Pennica D, Wood WI, Chien KR. Cardiotrophin-1 displays early expression in the murine heart tube and promotes cardiomyocyte survival. Development. 1996; 122: 419–428.[Abstract]
147. Foncea R, Galvez A, Perez V, Morales MP, Calixto A, Melendez J, Gonzalez-Jara F, Diaz-Araya G, Sapag-Hagar M, Sugden PH, LeRoith D, Lavandero S. Extracellular regulated kinase, but not protein kinase C, is an antiapoptotic signal of insulin-like growth factor-1 on cultured cardiac myocytes. Biochem Biophys Res Commun. 2000; 273: 736–744.[CrossRef][Medline] [Order article via Infotrieve]
148. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, Hewett TE, Jones SP, Lefer DJ, Peng CF, Kitsis RN, Molkentin JD. The MEK 1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 2000; 19: 6341–6350.[CrossRef][Medline] [Order article via Infotrieve]
149. Bishopric NH, Andreka P, Slepak T, Webster KA. Molecular mechanisms of apoptosis in the cardiac myocyte. Curr Opin Pharmacol. 2001; 1: 141–150.[CrossRef][Medline] [Order article via Infotrieve]
150. Fujio Y, Nguyen T, Wencker D, Kitsis RN, Walsh K. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation. 2000; 101: 660–667.
151. Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, Rosenzweig A. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J Biol Chem. 2002; 277: 22896–22901.
152. Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, Cantley LC, Izumo S. Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol. 2002; 22: 2799–2809.
153. Naga Prasad, Esposito G, Mao L, Koch WJ, Rockman HA. Gß
-dependent phosphoinositide 3-kinase activation in hearts with in vivo pressure overload hypertrophy. J Biol Chem. 2000; 275: 4693–4698.
154. Franchini KG, Torsoni AS, Soares PH, Saad MJ. Early activation of the multicomponent signaling complex associated with focal adhesion kinase induced by pressure overload in the rat heart. Circ Res. 2000; 87: 558–565.
155. Ivaska J, Nissinen L, Immonen N, Eriksson JE, Kahari V-M, Heino J. Integrin 2ß1 promotes activation of protein phosphatase 2A and dephosphorylation of Akt and Glycogen synthase kinase 3ß. Mol Cell Biol. 2002; 22: 1352–1359.
156. Tian B, Lessan K, Kahm J, Kleidon J, Henke C. ß1 integrin regulates fibroblast viability during collagen matrix contraction through a phosphatidylinositol 3-kinase/Akt/protein kinase B signaling pathway. J Biol Chem. 2002; 277: 24677–24675.
157. Negoro S, Oh H, Tone E, Kunisada K, Fujio Y, Walsh K, Kishimoto T, Yamauchi-Takihara K. Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through phosphatidylinositol 3-kinase/Akt phosphorylation and Bcl-xL/caspase-3 interaction. Circulation. 2001; 103: 555–561.
158. Oh H, Fujio Y, Kunisada K, Hirota H, Matsui H, Kishimoto T, Yamauchi-Takihara K. Activation of phosphatidylinositol 3-kinase through glycoprotein 130 induces protein kinase B and p70S6 kinase phosphorylation in cardiac myocytes. J Biol Chem. 1998; 273: 9703–9710.
159. Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KDR, Schaefer E, Kajstura J, Anversa P, Sussman MA. Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ Res. 2001; 88: 1020–1027.
160. Kim C-H, Cho Y-S, Chun Y-S, Park J-W, Kim M-S. Early expression of myocardial HIF-1 in response to mechanical stress: regulation by stretch activated channels and the phosphatidylinositol 3-kinase signaling pathway. Circ Res. 2002; 90: 25–33.[CrossRef]
161. Haq S, Choukroun G, Kang ZB, Ranu H, Matsui T, Rosenzweig A, Molkentin JD, Alessandri A, Woodgett J, Hajjar R, Michael A, Force T. Glycogen synthase kinase-3ß is a negative regulator of cardiomyocyte hypertrophy. J Cell Biol. 2000; 151: 117–130.
162. Wang L, Wang X, Proud CG. Activation of mRNA translation in rat cardiac myocytes by insulin involves multiple rapamycin-sensitive steps. Am J Physiol Heart Circ Physiol. 2000; 278: H1056–H1068.
163. Mehrhof FB, Muller FU, Bergmann MW, Li P, Wang Y, Schmitz W, Dietz R, von Harsdorf R. In cardiomyocyte hypoxia, insulin-like growth factor-I—induced antiapoptotic signaling requires phosphatidylinositol-3-OH-kinase—dependent and mitogen-activated protein kinase—dependent activation of the transcription factor cAMP response element-binding protein. Circulation. 2001; 104: 2088–2094.
164. Esposito G, Rapacciuolo A, Naga Prasad SV, Takaoka H, Thomas SA, Koch WJ, Rockman HA. Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation. 2002; 105: 85–92.
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