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(Circulation Research. 2001;88:1112.)
© 2001 American Heart Association, Inc.

Review

Integrins and the Myocardium

Robert S. Ross, Thomas K. Borg

From the Departments of Physiology, Medicine, and The Cardiovascular Research Laboratories (R.S.R.), UCLA School of Medicine, Los Angeles, Calif; and Department of Developmental Biology & Anatomy (T.K.B.), School of Medicine, University of South Carolina, Columbia, SC.

Correspondence to Robert S. Ross, University of California–Los Angeles School of Medicine, Department of Physiology, Center for the Health Sciences, Room 53-231, 10833 Le Conte Ave, Los Angeles, CA 90095-1751. E-mail rross{at}mednet.ucla.edu

	Abstract

Top Abstract Introduction Integrin Structure Integrin Function and Expression Integrins in Cardiac Development Integrin Expression in Cardiac... Integrin Signaling in the... Summary and Future Directions References

 
Abstract—Extracellular matrix provides a structural, chemical, and mechanical substrate that is essential in cardiac development, growth, and responses to pathophysiological signals. Transmembrane receptors termed integrins provide a dynamic interaction of environmental cues and intracellular events. Integrins orchestrate multiple functions in the intact organism including organogenesis, regulation of gene expression, cell proliferation, differentiation, migration, and death. They are expressed in all cellular components of the cardiovascular system, including the vasculature, blood, cardiac myocytes and nonmuscle cardiac cells. The focus of this review will be on the role of integrins in the myocardium. We will provide background on integrin structure and function, discuss how the expression of integrins is critical to the form and function of the developing and postnatal myocardium, and review the known data on integrins as signaling molecules in the heart. Finally, we will offer insights to the future research directions into this important family of extracellular matrix receptors in the myocardium.

Key Words: integrin • myocardium • extracellular matrix

	Introduction

Top Abstract Introduction Integrin Structure Integrin Function and Expression Integrins in Cardiac Development Integrin Expression in Cardiac... Integrin Signaling in the... Summary and Future Directions References

 
Extracellular matrix (ECM) provides a structural, chemical, and mechanical substrate that is essential in cardiac development, growth, and responses to pathophysiological signals. Transmembrane receptors termed integrins provide a dynamic interaction of environmental cues and intracellular events.^{1 2 3} Integrins orchestrate multiple functions in the intact organism including organogenesis, regulation of gene expression, cell proliferation, differentiation, migration, and death. They are expressed in all cellular components of the cardiovascular system, including the vasculature, blood, cardiac myocytes, and nonmuscle cardiac cells. The focus of this review will be on the role of integrins in the myocardium, because their function in the vasculature and platelets has been recently reviewed.^{4 5} We will discuss how the expression of integrins is critical to the form and function of the myocardium, evaluate potential mechanisms of action of the integrins in the regulation of these processes, and offer insights to the future research directions into this important family of ECM receptors in the myocardium.

	Integrin Structure

Top Abstract Introduction Integrin Structure Integrin Function and Expression Integrins in Cardiac Development Integrin Expression in Cardiac... Integrin Signaling in the... Summary and Future Directions References

 
Integrins are noncovalently associated heterodimeric transmembrane receptors composed of and ß subunits, with subunits ranging from 120 to 180 kDa whereas ß subunits are 90 to 110 kDa.^{3 6} Historically, integrins were identified based on an initial series of experiments suggesting a physical association between fibronectin and the intracellular cytoskeleton.⁷ Subsequently, studies were published from several laboratories that (1) identified glycoproteins having characteristics of membrane proteins, and (2) showed that antibodies which recognized these proteins could inhibit cellular adhesion.^{8 9 10 11 12} These observations led to the cloning of chick fibroblast cDNAs that encoded for a molecule involved in transmembrane linkage between fibronectin and actin.¹³ Previous literature about this important glycoprotein had used terminology ranging from CSAT or JG22 antigen^{14 15} to 140 kd complex or fibronectin receptor.^{8 11} To resolve the confusion and proceed with a unified definition, the cloned molecule was termed "integrin" because it was both an integral membrane protein and involved in cellular and ECM integrity.¹³

Integrin subunits consist of a large extracellular domain (700 to 1100 amino acids), a single transmembrane segment, and short cytoplasmic tails, ranging from 20 to 60 amino acids.¹⁶ It is through this short cytoplasmic domain that integrins signal (see below). The structure of a generic integrin is shown in the Figure, panel A. For additional data on detailed integrin structure, the reader is referred to the excellent reviews by Humphries and colleagues.^{16 17}

View larger version (39K): [in this window] [in a new window]   Figure 1. A, Block diagram of integrin heterodimer structure. Both the and ß subunits are single-transmembrane spanning proteins with generally short cytoplasmic domains. The N-terminus of subunits is composed of 7 repeats. Included in these repeats are 3 or 4 divalent cation binding sites termed an "EF hand." Beyond this, subunits might be divided into two groups. One group has a 200-AA insertion termed an "A-domain module," which contains a metal ion–dependent adhesion site or MIDAS.102 A second group contains a posttranslational proteolytic cleavage site, which when recognized and cleaved, can convert these subunits into heavy chain/light chain dimers held together by disulfide bonds.16 Like many of the subunits, the ß subunits also contain an A-domain in the amino portion of their extracellular region, likewise containing a MIDAS. The carboxy-terminus of the ß subunit extracellular domain contains 4 cysteine-rich domains that are themselves internally disulfide-bonded. Numerous other sites within the subunits have been identified by a combination of mutagenesis, chimera formation, and antibody-binding studies. These include regions critical for subunit dimerization, integrin-ligand interaction, and integrin activation. TM indicates transmembrane segment; Cyto, cytoplasmic domain. B, Diagrammatic representation of outside-in signaling of integrins. The inactive integrin heterodimer is depicted on the left-most portion of the Figure. After ligand binding (eg, of laminin, shown in yellow), the integrin conformation is altered and subsequently the heterodimer can participate in events critical for organization of the cytoskeleton and other intracellular signaling events that might be important for cell survival or initiation/propagation of cardiac myocyte hypertrophic events. Thus, mechanical tension outside the cell could be converted to intracellular biochemical signals through the integrins. For this process, the cytoplasmic domain of the integrin subunits signals through a host of molecules such as kinases (FAK, Akt, Raf, MEK, ERK [shown in olive]), cytoskeletal organizers (eg, paxillin), small GTPases (eg, Rho, Rac, Ras [shown in blue]), and other molecules. Cytoplasmic domain–binding proteins have also been identified, some of which are dominantly expressed in striated muscle (eg, MIBP or melusin) but whose function is still incompletely understood. C, Diagrammatic representation of inside-out signaling of integrins. In addition to extracellular events causing integrin-mediated intracellular signaling events, intracellular signals can cause the integrins to alter their ability to bind to the extracellular matrix. This is termed "inside-out" signaling. An agonist might bind to a nonintegrin receptor such as illustrated on the left portion of the Figure. This receptor in turn mediates intracellular signaling events and may also cause cytoskeletal organization. In turn, this leads to binding of an integrin activation complex to the cytoplasmic domain of the integrin subunits. In (1), binding of the integrin activation complex causes a conformational change in the integrin subunits leading to increased affinity of matrix binding (laminin [yellow)]. In (2), binding of the integrin activation complex leads to integrin clustering and increased avidity of integrin-matrix binding, perhaps causing a more permanent binding of integrins to matrix (here depicted by laminin).

Integrins comprise a large family of cell surface receptors with more than 18 and 8 ß subunits identified in mammals. Although the selective mechanism of subunit pairing has not been absolutely proven, it is clear that not all combinations of /ß heterodimers can form. Despite this, more than 24 paired integrin receptors have been identified to date. Additional complexity is introduced by the numerous splice variant isoforms of individual subunits, including some expressed in the heart.^{18 19 20} Of this large family, the relative number of specific and ß chains in the myocardium is small. In myocytes, ₁, ₃, ₅, ₆, ₇, ₉, and ₁₀ are expressed. In the heart, expression of even these subunits can be temporally modified and developmentally regulated. For example ₁ and ₅ integrin subunits are expressed in the embryonic heart, become downregulated postnatally, and can be reinduced after mechanical loading of the heart through aortic constriction. These individual chains seem to be associated only with splice variants of ß₁ integrin, including the splice variant ß_1D, which is dominantly expressed in striated muscle and is the prime ß₁ integrin isoform expressed in postnatal heart.^{21 22} The expression of ß₃ and ß₅ on myocytes, as opposed to their more traditional localization in the vasculature, has been detected by some authors.²³ The varied detection of ß₁, ß₃, and ß₅ expression obtained by different laboratories may be dependent on the unique antibodies (and their specificities) used by different investigators.

Cardiac fibroblasts express a repertoire of subunits like that of the cardiac myocyte, but they do not express ₆ and ₇ as these cells have no laminin-containing basement membrane. In contrast, _v and the collagen-specific ₂ subunit appear to be uniquely expressed by the cardiac fibroblasts but not by cardiac myocytes.^{24 25 26}

	Integrin Function and Expression

Top Abstract Introduction Integrin Structure Integrin Function and Expression Integrins in Cardiac Development Integrin Expression in Cardiac... Integrin Signaling in the... Summary and Future Directions References

 
Integrins are fundamental components in the interaction between the ECM and the cardiac myocytes or fibroblasts. They have several functions that include the regulation of cellular phenotype in the developing and postnatal myocardium, adhesion, and migration. A most intriguing role of integrins in the heart is their ability to serve as mechanotransducers during normal development and in response to physiological and pathophysiological signals.^{27 28 29 30}

The repertoire of integrins that are expressed on a particular cell type, and even in subcellular regions, can be unique and can vary in a temporal manner. The diversity of different combinations of /ß heterodimers supplies a means to direct varied functional roles for the integrins during such events as cardiac development or the onset of pathological conditions. A single integrin receptor can bind to one or several ligands and in addition, a single ligand can be bound by several integrin heterodimers. For example, two integrins expressed on cardiac myocytes are ₃ß₁ and ₅ß₁. ₃ß₁ can bind to collagen I, fibronectin, and laminin, whereas ₅ß₁ is dominantly a fibronectin-binding integrin. Further, cardiomyocyte ₁ß₁, ₃ß₁, and ₇ß₁ all bind laminin, whereas fibroblast-expressed ₅ß₁ and _vß₁ (expressed in the vasculature) are fibronectin-binding integrins. The ability of individual ECM components such as fibronectin or interstitial collagen to bind several integrin heterodimers may represent functional redundancy but also could allow specific function of distinct integrin subsets.

Integrins were initially shown to function only as cell-matrix adhesion molecules,¹³ but it has become well accepted that they are important signal transducers.^{3 4 31} ECM-integrin interactions function in a bidirectional manner across cell membranes. The binding of integrins to an ECM component results in intracellular signaling events. As the extracellular domain of integrin receptors becomes occupied by ligand and cluster, the integrins set off a cascade of events termed "outside-in" signaling (Figure, panel B). In this regard, they can influence a wide range of activities including alterations in cell morphology, migration, proliferation, differentiation, survival; gene expression, suppression of tumorigenicity, changes in intracellular pH, or concentration of cytosolic Ca²⁺. As an example, laminin binding to ß₁ integrins has been linked to regulation of L-type Ca²⁺ channels through both adrenergic and cholinergic receptors in cultured atrial myocytes.^{32 33}

Because the integrins do not themselves possess enzymatic activity, to signal, they must trigger downstream molecules.^{2 31 34} Examples include activation of tyrosine kinases such as pp125 focal adhesion kinase (FAK) or small GTPases such as Rho or Rac and regulation of cytoskeletal components such as talin, paxillin, or p130^CAS. The integrin cytoplasmic domain is essential in this process and has been shown to bind numerous molecules. These include calreticulin and FAK, as well as melusin and muscle integrin-binding protein (MIBP), both of which are preferentially expressed in muscle.^{35 36 37 38} Additionally, integrin cytoplasmic tails bind directly to components of the cytoskeleton such as talin and -actinin. Ultimately, signaling from the integrins may influence pathways through which other cellular effectors (such as growth factors) may also signal, including those requiring Akt, Raf, phosphoinositide 3-kinase (PI3-K), or mitogen-activated protein kinases (MAPKs)/extracellular signal–regulated kinases (ERKs).

In addition to outside-in signaling, integrin function can be modified by agonists that bind to nonintegrin cellular receptors and in turn modify integrin activation, a process termed "inside-out" signaling (Figure, panel C). This process has been best characterized in platelets because antibodies are available that bind specifically to activated platelet integrins. In platelets, agonists such as thrombin, ADP, epinephrine, or thromboxane A₂ might activate phospholipase Cß through heterotrimeric G proteins. This is followed by phosphatidylinositol hydrolysis and production of diacylglycerol and inositol-3-phosphate.⁵ Theses events lead to both increased binding of integrin to ligand as well as clustering of multiple integrins in close spacing within the cell membrane. Although not definitively proven, these events initiated by the nonintegrin receptors, have been hypothesized to cause alterations in the intracellular, membrane-proximal region of the integrin cytoplasmic domain, subsequent transmission of information across the membrane to extracellular integrin domains, and then a conformational change and conversion of the integrin from a low to a high activation state. The modulation of activation state may actually alter two discrete processes, ie, affinity and avidity.^{5 39} In this scenario, integrin affinity relates conformational changes in the integrin heterodimer to strength of ligand binding, akin to that which can be measured as the strength of interaction between antigen and antibody in solution. Avidity on the other hand may be related to agonist-mediated clustering of multiple integrin heterodimers in the cell membrane. When clustered receptors are in place in the membrane, the receptor displays a higher apparent affinity (termed "functional affinity" or "avidity"), which relates the density of the receptor cluster to the strength of ligand binding.³⁹ Thus, through inside-out signaling, integrins can undergo a switch from a low affinity/avidity state to a high affinity/avidity state. Morphologically, this clustering is apparent in the localization of integrins on myocytes.⁴⁰ In these cells, integrins are detected in an area near the Z band where they colocalize with cytoskeletal components and signaling complexes.⁴⁰ The Z-band localization in vivo is analogous to the focal adhesion in vitro. This localization supports the hypothesis that integrins are involved in mechanical signaling as well as maintenance of the cellular phenotype. In fibroblasts, the integrins are localized to the focal adhesion in vitro and to an analogous region in vivo. Overall, in both myocytes and fibroblasts, integrin clustering is associated with sites of chemical and mechanical signaling.

	Integrins in Cardiac Development

Top Abstract Introduction Integrin Structure Integrin Function and Expression Integrins in Cardiac Development Integrin Expression in Cardiac... Integrin Signaling in the... Summary and Future Directions References

 
Cellular interactions with the ECM are essential to normal formation of the heart.^{41 42 43 44} In this regard, epidermal growth factor (EGF)–mediated proliferation of human fetal ventricular myocytes has specifically been linked to adhesion through ß₁ integrins, particularly ₁ß₁ and ₅ß₁.⁴² ß₃ integrins did not appear to be involved in this proliferative response. The expression pattern of integrins during heart development indicates that there is a coordinated expression of both ECM substrate and specific integrins.^{45 46}

The role of specific integrins in vivo during cardiac development is still poorly understood. However, from other systems, it is clear that the temporal and spatial expression of integrins could be critical in defining appropriate cellular-ECM interactions during organogenesis. It is not only the presence or absence of integrins but their precise spatial and temporal expression that is critical for proper organ formation. These events are still poorly understood in the heart. Integrins are necessary for proper myofibrillar patterning. In vitro studies have shown that the arrangement of collagen and the presence of ₁ß₁ are critical in formation of the rod-shaped phenotype.⁴⁷ Disruption of ₁ß₁ function by antibodies or adenovirally mediated inhibition resulted in altered phenotype of cultured myocytes as well as altered patterning of their myofibrils. Regulation of the myofibrillar pattern in vivo likely also involves the appropriate expression of specific integrins.

The genetic ablation of several integrin subunits has clearly shown that they are essential for normal development and function.^{48 49 50 51} Knockouts of ß₁ integrin resulted in early embryonic death soon after blastocyst implantation, clearly demonstrating the essential function of this subunit.^{52 53} Further, manipulation of the different isoforms of ß₁ integrin has shown that the ß₁ integrin isoform that is dominantly expressed in striated muscle (ß_1D) has a unique, yet poorly understood function. Complete replacement of the ubiquitously expressed ß_1A integrin with the ß_1D isoform was performed through a series of clever knockin/knockout experiments and resulted in embryonic death.⁵⁴ Our own work has shown that reduction, but not complete ablation, of ß₁ specifically in cardiac myocytes leads to progressive decrease in postnatal cardiac function and development of heart failure.⁵⁵ ₄ integrin null mice die in utero with two developmental abnormalities: failure of chorioallantoic fusion and also abnormal formation of the epicardium and coronary vessels.⁵¹ Functional redundancy of some integrins clearly exists in the heart. For example, in contrast to the in vitro experiments mentioned above, knockout of ₁ integrin has no effect on murine viability and also no easily detectable cardiac phenotype, despite ₁ being an important receptor for collagen and laminin in the prenatal and stressed myocyte.⁵⁶

	Integrin Expression in Cardiac Disease

Top Abstract Introduction Integrin Structure Integrin Function and Expression Integrins in Cardiac Development Integrin Expression in Cardiac... Integrin Signaling in the... Summary and Future Directions References

 
Cellular-ECM interactions in the adult heart provide a structural, chemical, and mechanical substrate that is essential for normal homeostasis and adaptations to pathophysiological signals. Because integrins are the principal receptors for the ECM, their appropriate expression and function are likely to be necessary for normal cardiovascular function in the adult. As with embryonic and fetal development, integrin expression appears to be closely coordinated with ECM expression in the adult heart. However, it would be naïve to assume that the adult pattern of expression is the same as in the embryo, because the physiological signals in the adult are different in magnitude and duration. As an example, in models of cardiac hypertrophy, dilated cardiomyopathy, and myocardial infarction, dramatic changes occur in the arrangement of extracellular matrix components. Altered expression of collagens, fibronectin, osteopontin, tenacin, and other ECM components have been documented.^{57 58 59 60 61 62 63 64} The expression of specific integrins has not been examined extensively in all of these examples, but when studied, integrins also show an altered pattern. However, it is not clear whether the altered integrin localization is a primary response or one commensurate with the changes in ECM component(s).

Multiple factors are responsible for the hypertrophic response, and integrins are an important part of the process. Studies have directly linked ß₁ integrin (both isoforms A and D) to the hypertrophic response of neonatal ventricular myocytes, in that overexpression of these integrins could induce this in vitro hypertrophic response or augment one caused by ₁ adrenergic agents, whereas inhibition of ß₁ function and signaling reduced the adrenergically mediated hypertrophy.^{65 66} Further, adrenergic stimulation of isolated neonatal ventricular myocytes increased expression of ß_1D integrin >350%.⁶⁵ In vivo, integrin profiles have begun to be assessed in the intact myocardium of both rats and mice provoked to undergo morphological cardiac hypertrophy with aortic constriction.^{25 67} In these rodent systems, increased expression of ß_1A and ß_1D, ₃, and _7ß were detected, as was reexpression of ₁ and ₅ integrins, subunits that are expressed during development but downregulated in the normal adult myocardium. Pressure overload of the cat right ventricle through pulmonary artery banding has also shown mobilization of ß₃ integrin to the cytoskeletal fraction of lysed myocardial tissue 4 hours after banding and both the cytoskeletal and membrane-bound fractions by 48 hours after pressure overload. However, the levels returned to baseline by 1 week.⁶⁸ Extensive evaluation of integrin expression patterns in cardiac failure has not been performed.

The interaction of fibroblasts with cardiac myocytes and the ECM has been addressed both in vivo⁶⁹ and in vitro.^{70 71 72 73 74 75} These studies have demonstrated that both mechanical stimulation⁷¹ and a variety of growth factors upregulate the expression of several integrins as well as specific ECM components including interstitial collagens, osteopontin, fibronectin, and laminin. These growth factors, including platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), angiotensin II (Ang II), and transforming growth factor-ß (TGF-ß) appeared to modulate expression in a paracrine or autocrine fashion. However, the precise signaling pathways through which these growth factors interact with integrin receptors on cardiac myocytes is not fully understood. Similarly, mechanical or chemical (growth factors, hormones, and cytokines) stimulation of cardiac fibroblasts is also associated with induction of matrix metalloproteinases (MMPs). This induction may also influence integrin functions because the MMPs have the potential to modify ECM substrates as well as cell surface receptors.

Significant remodeling of the extracellular matrix occurs in the acute (healing) and chronic (remodeling) stages after myocardial infarction (MI).^{76 77 78 79 80 81} Undoubtedly, as the interface between cells and ECM, integrins are also involved in this process. Initial work has been performed to evaluate the changes in several integrin subunits after MI in the rat.⁸² Like the effect of pressure overload, by 7 days after MI, the ₁ integrin was reexpressed in both the remaining normal myocytes in the peri-infarct zone and also in remodeled tissue in the infarct zone itself. Peri-infarct expression of ₁ remained elevated at 6 weeks after MI. No change was found in ₃ expression, whereas ₅ integrin increased its expression in both peri-infarcted and noninfarcted myocardial tissue through day 7, returning to pre-MI levels by 2 weeks after MI. Given that this expression pattern is distinct from that which occurs after pressure overload, it is unlikely that this response is simply due to hypertrophic induction of the integrins. Perhaps after MI, integrin expression from myocytes is modulated by paracrine release of factors such as Ang II, like that identified to occur in cardiac fibroblasts.^{73 83} Further work is clearly needed to identify the role of integrins in the post-MI remodeling process.

In models of hypertrophy, dilation, and failure, the cardiac myocyte undergoes dramatic changes in cell shape. To accommodate to the change in cellular shape/phenotype, integrins must change their position on the cell surface. The contact of the integrins with the ECM as well as with the cytoskeleton must also change.^{40 84} During normal development or with initial physiological adaptation such as occurs with the onset of pressure overload, there appears to be coordinated cellular and subcellular localized expression of ECM and integrins. However, as the myocardium makes the transition from compensated to decompensated heart failure, an imbalance in this ECM-integrin coordination may occur. For example, during the initial phases of pressure overload, expression of fibronectin and its prime integrin receptor, ₅ß₁, increase in parallel. However, in later stages of hypertrophic induction, characterized by myocyte branching, there appears to be a mismatch of fibronectin and ₅ß₁ expression.⁸⁵ The disruption of coordinated connection between fibronectin and its integrin receptor may lead to cardiac myocytes being released from their ECM attachment sites, resulting in apoptosis. This process, termed anoikis⁸⁶ (Greek for "homelessness") has been described in epithelial cells and was proposed to be responsible for selective myocyte death in the heart.⁸⁴ It is likely that the alteration of the ECM-integrin-cytoskeletal complex could subject the cell to altered mechanical forces that would also be detrimental to survival.

Release or shedding of integrins into the extracellular space has been reported during the transition from cardiac hypertrophy to heart failure, indicating that as the myocyte changes shape, it can release a portion of the extracellular domain of its integrins.⁸⁴ The mechanism involved in the release of the integrin is not known but could involve a class of enzymes known as shedases, extracellular proteases that include a disintegrin and metalloproteinase (ADAM)s, as well as the MMPs.^{87 88 89} The ADAMs could serve to release the ectodomain from the intact integrin and to allow for a new integrin-ECM site to form. At present, the functional role of this cleaved integrin is poorly understood.

	Integrin Signaling in the Myocardium

Top Abstract Introduction Integrin Structure Integrin Function and Expression Integrins in Cardiac Development Integrin Expression in Cardiac... Integrin Signaling in the... Summary and Future Directions References

 
As mentioned above, integrins signal bidirectionally across the cell membrane and do not possess intrinsic kinase activity. How they signal is still incompletely understood, but it is likely that integrin-mediated signaling events are cell-type specific. To date, only limited data are available on integrin signaling in the myocardium. Our own work has shown that disruption of integrin signaling in cultured neonatal rat ventricular myocytes (NRVMs) can disrupt adrenergically mediated hypertrophic growth.^{65 66} As an extension of this work, we and others have shown that FAK, a primary mediator of integrin signaling, plays a role in the hypertrophic and adhesive response of NRVMs and also can be activated by vascular endothelial growth factor (VEGF).^{65 90 91 92 93} Adrenergic agonist–mediated activation of ERK1/2 and other hypertrophic responses are significantly blunted by a dominant inhibitor of FAK.^{66 90} Taken together, these data suggest that integrin signaling may converge with other hypertrophic agonists through ERK1/2 in the cardiomyocyte.

Similarly, the mechanotransductive properties of integrins have been demonstrated in studies where cultured rat cardiac fibroblasts were subjected to stretch.⁹⁴ ERK2 and c-Jun N-terminal kinase (JNK1) activation occurred after fibroblast stretch. Stretch-mediated ERK2 phosphorylation could be blocked only by a combination of ₄ and ₅ antibodies and RGD peptide, but these inhibitors had no effect on ERK2 when used individually. Further, they did not alter JNK1 activation, even when used combinatorially. No effect of stretch on p38 activation was noted. The upstream activators of these kinases, eg, FAK, were not investigated. Thus, whether cardiac myocyte or cardiac fibroblast integrins (at least in these culture models) act primarily through an FAK-mediated pathway or through alternative integrin-binding proteins is poorly understood.

Several groups have begun to examine integrin signaling in the intact heart.^{68 95 96 97 98} Extending our in vitro work, we disrupted cardiac myocyte integrin function in transgenic mice utilizing a dominant-negative inhibitor termed Tacß1.⁹⁹ High-level transgene expression resulted in replacement fibrosis of the myocardium and perinatal death, likely from cell-ECM detachment. Surviving lines with lesser amounts of transgene expression showed reduced ventricular contractility and relaxation, reduced levels of basal FAK phosphorylation, and blunted activation of ERKs after aortic constriction. Similar results with regard to perinatal lethality and replacement fibrosis were detected in a cardiac-specific transgenic mouse that overexpressed a gain-of-function ₅ integrin.¹⁰⁰ No abnormalities were found when the wild-type ₅ integrin was overexpressed. Expression of the ₅ mutant may lead to cardiac phenotypic change by causing either unrestrained production of an integrin-mediated signal or perhaps by pairing with ß subunits, leading to production of a dominant-negative molecule akin to the Tacß1, above.

In agreement with this work, a series of studies have been performed to analyze integrin signaling in a pulmonary artery banded (PAB) cat model.^{68 97 98} These authors showed that PAB effected cytoskeletal association and phosphorylation of FAK, as well as c-Src, recruitment of the adaptor proteins p130^Cas, Shc and Nck, and activation of ERK1/2. In this species, ß₃ and ß₁ integrin were linked to these downstream cytoskeletal/integrin-mediated signaling events.²³ Franchini et al⁹⁵ showed that FAK activation and assembly of a signaling complex, consisting of FAK, c-Src, Grb2, and PI3-K, followed aortic banding of rats. Pressure overload also activated ERK1/2 and Akt. As further evidence of the importance of this integrin-linked signaling complex that assembles in the focal adhesion, transgenic mice, which express constitutively active rac1 in the cardiac cell, have focal adhesion remodeling and develop perinatal dilated cardiomyopathy.¹⁰¹

	Summary and Future Directions

Top Abstract Introduction Integrin Structure Integrin Function and Expression Integrins in Cardiac Development Integrin Expression in Cardiac... Integrin Signaling in the... Summary and Future Directions References

 
It is clear that the integrins represent a complex family of receptors that serve important adhesive and signaling functions. Their mechanism of action in the myocardium is only beginning to be understood. They appear to play crucial roles in providing cues and positional information that are necessary for myofibrillogenesis, organogenesis, and homeostasis of normal cardiac function. Future in vitro and in vivo studies are required to understand certain questions:

1. Through which pathways do integrins signal in the heart, and specifically what are the functions of striated muscle–restricted integrins and integrin-binding proteins?
   
2. Do integrin receptors interact with other known signaling pathways in the myocardium as either structural organizers or to synergize in effecting downstream signaling events?
   
3. What is the importance of integrins as mechanotransducers in the myocardium?
   
4. How do the integrins provide directional cues for cell migration, chemotaxis, and induction (response) to external signals, and specifically what is the role of integrin shedding in these processes?
   
5. How does the varied temporal and spatial expression pattern of integrins influence myocardial development, adaptation, and compensatory responses to pathological insults and disease progression?
   
6. What is the role of other ECM-modifying molecules such as MMPs, tissue inhibitors of metalloproteinases (TIMPS), and ADAMs in modifying myocardial integrin expression and function?
   

Great advances have been made in understanding general integrin biology. Our present molecular, cellular, and genetic tools and models should allow us to make great advances in defining the importance of integrin function in myocardial development, maintenance, and disease.

	Acknowledgments

 
This work was supported by grants from the National Institutes of Health (HL-57872 to R.S.R.; HL-37669 and HL-59981 to T.K.B.), the American Heart Association, and the UCLA Laubisch Cardiovascular Research Fund. The authors would like to acknowledge the helpful remarks of the following individuals: Louis Terracio, Edie Goldsmith, Alex McFadden, Robert Price, Wayne Carver, Kirk Knowlton, Bev Lorell, and Allen Samarel.

	Footnotes

 
Original received February 27, 2001; revision received April 20, 2001; accepted April 20, 2001.

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Top Abstract Introduction Integrin Structure Integrin Function and Expression Integrins in Cardiac Development Integrin Expression in Cardiac... Integrin Signaling in the... Summary and Future Directions References

 
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