© 1998 American Heart Association, Inc.
Editorial |
Angiotensin and Endothelin
Messengers That Couple Ventricular Stretch to the Na+/H+ Exchanger and Cardiac Hypertrophy
Correspondence to David E. Dostal, PhD, Pennsylvania State College of Medicine, Henry Hood MD Research Program, Sigfried and Janet Weis Center for Research, 100 North Academy Ave, Danville, PA 17822. E-mail ddostal{at}psghs.edu
Key Words: angiotensin II • endothelin-1 • Na+/H+ exchanger • mechanical stretch • myocardium
Changes in intracellular pH (pHi) can produce marked effects on cardiac function, and, therefore, it is important that the cell possess mechanisms by which pHi is regulated, especially after intracellular acidosis associated with myocardial ischemia. The Na+/H+ exchanger (NHE) and the Na+/HCO3- symport represent the 2 major pathways by which alkalinization occurs in cardiac cells. The NHE not only regulates pHi but also cell volume and intracellular signaling in response to a variety of stimuli.
Na+/H+ Exchanger and Cardiac Growth
The NHE in mammalian
myocardium1 has received considerable
attention in the past decade, because it has been linked to cardiac
growth and reperfusion injury.2 3 The NHE is
activated by mechanical stretch in cultured cardiac myocytes
and is thought to be a primary factor in influencing the anabolic state
of the ventricular myocardium in response to
pressure overload.4 5 Activation of the NHE
occurs via phosphorylation of the cytoplasmic domain,
which appears to be mediated by protein kinase
C.6 Mechanical stretch of neonatal cardiac
myocytes has also been associated with activation of second messengers,
such as inositol triphosphate, protein kinase C, Raf-1 kinase, and
mitogen-activated protein (MAP) kinase, all of which can
contribute to reexpression of a number of fetal genes associated with
cardiac hypertrophy, including ß-myosin heavy chain,
skeletal 
-actin, and atrial natriuretic
peptide.7 In studies using neonatal rat cardiac
myocytes cultured on elastic membranes, stretch-mediated increases in
MAP kinase activity and protein synthesis were attenuated by treatment
of cells with the NHE antagonist Hoe
694,2 8 suggesting that the NHE has an important
role in mediating growth in the pressure-overloaded
myocardium.
Mechanical Stretch and Activation of the Na+/H+ Exchanger
Deformation of the cardiac myocyte as it occurs in vivo, or in vitro under experimental or pathological conditions, presents a mechanical stress for cellular structures. This mechanical loading is an important physiological stimulus for cardiac hypertrophy. In this issue of Circulation Research, Cingolani et al9 have examined the effects of mechanical stretch on activation of the NHE in a multicellular preparation from adult feline heart. NHE activity was obtained by bathing the tissue in HEPES buffer, which excluded intracellular acidification due to activation of the Na+-independent Cl-/HCO3- exchanger. This model also obviated any angiotensin II (Ang II) effects on alkalinization resulting from activation of the Na+/HCO3- symport via the AT2 receptor.10 This latter observation is important, given that the AT2 receptor has been shown to oppose AT1-mediated actions in multiple cell types. The authors demonstrated that in acutely stretched feline right ventricular papillary muscle, NHE activation occurred as a result of Ang II and endothelin-1 (ET-1) release/production. Ang II–induced hypertrophic phenotypes in cultured cardiac myocytes, together with the ability of AT1 receptor antagonists to block stretch-induced hypertrophic responses,11 strongly argue for a role of Ang II in mechanically induced growth. Ang II is associated with improvement of mechanical behavior and calcium transients of cardiac myocytes,12 13 stimulation of cardiac hypertrophy,13 14 15 and activation of myocyte apoptosis.16 17 Likewise, ET-1 has been shown to modulate myocyte contraction,18 stimulate growth-related signaling pathways,19 and activate the NHE.20 However, it remains to be determined whether Ang II and ET-1 will be important extracellular messengers for evoking acute stretch-mediated responses, using in vivo models of cardiac hypertrophy.
How Does Mechanical Stretch Couple to Intracardiac Peptide Secretion/Production?
Data from immunoelectron microscopy, combined with analysis of extracellular media, suggest that acute stretch stimulates secretion of prestored Ang II from cardiac myocytes but not fibroblasts.11 The mechanosensor, proximal signaling mechanisms, and associated autocrine secretory pathways remain unknown. Increases in intracellular calcium, demonstrated to occur in cardiac myocytes subjected to mechanical deformation,21 could be involved in the release of Ang II, ET-1, and other factors. Increased levels of intracellular calcium are involved in endocytotic vesicle fusion and release of a number of peptides and cytokines in other cell types.22 23 However, blockade of the stretch-sensitive ion channel appears to have no effect on stretch-induced activation of the NHE in neonatal rat cardiac myocytes,8 suggesting that this mechanism has a minor role in stretch-induced release of Ang II or ET-1. Mechanical forces could also mediate secretion via cytoskeletal-related mechanisms. Mechanical stretch evokes tyrosine phosphorylation of focal adhesion kinase in mesangial cells,24 and integrins have been implicated as mechanotransducers that couple to tyrosine phosphorylation of intracellular proteins associated with focal adhesions.25 In cardiac tissue, ß3 integrin is upregulated in association with right ventricular pressure overload,26 and ß1 integrin has been directly linked to cellular hypertrophy of neonatal rat cardiac myocytes.27
Is Stretch-Induced Release of Ang II and ET-1 an Autocrine or Paracrine Process?
The origin of extracellular Ang II and ET-1 in stretched myocardial preparations, such as the feline papillary muscle used by Cingolani et al,9 remains to be determined. Feline papillary muscle is multicellular and therefore functions as a syncytium of cardiac myocytes, which is surrounded by support cells consisting primarily of fibroblasts and endothelial cells. All 3 cell types have been shown to produce Ang II11 28 29 and ET-118 19 30 under in vitro conditions. In addition, these cardiac cells express AT1 and ET-1 receptors that may couple to autocrine secretion/production.18 30 31 32 The work of Sadoshima et al11 suggests that cardiac myocytes are the only source of Ang II during acute stretch. In cardiac fibroblasts subjected to prolonged stretch, there is upregulation of renin and angiotensinogen mRNA levels at 8 hours (D. Dostal et al, unpublished data, 1998) and increased production of extracellular Ang II and ET-1 at 48 hours.33 However, it remains to be determined whether cardiac Ang II and ET-1 levels are regulated by similar mechanisms in the pressure-overloaded myocardium.
Growth and Cross-Talk Among Cardiac Factors
In the work of Cingolani et al,9 both Ang II and ET-1 were involved in stretch-induced activation of the NHE. Likewise, in pressure overload cardiac hypertrophy, several humoral/autocrine/paracrine systems are activated,7 suggesting that cross-talk between synergistic and opposing signaling pathways constitutes the predominant form of regulation under these conditions. With cooperative interactions among growth factors,33 34 elimination of a single system (eg, Ang II, ET-1, cytokines), using transgenic technology, would be expected to fail in preventing pressure overload–induced cardiac hypertrophy. Nyui et al35 showed that myocytes from angiotensinogen knockout mice readily activated the MAP kinase pathway in response to mechanical stretch, whereas in wild-type myocytes, this response was inhibited by an AT1 receptor antagonist. In myocytes from the angiotensinogen knockout mice, stretch-induced MAP kinase activation now occurred via a cytokine-gp130 autocrine pathway36 instead of by Ang II. In fact, the gp130-mediated pathway more efficiently coupled stretch to MAP kinase activity in myocytes from transgenic mice compared with wild-type. Another transgenic model, in which there may be compensation for a functional loss of Ang II actions, is the AT1A knockout mouse.37 In this study, the AT1A receptor was not necessary for pressure overload–induced cardiac hypertrophy. It could be argued that the cardiac AT1B receptor mediated the hypertropic response, because this receptor appears to be functionally equivalent to the AT1A. This was not tested in the study through the use of an AT1 receptor antagonist. It is also possible that another local or endocrine system may have "stepped in" to substitute for AT1A receptor effects. Refinement of transgenic approaches, such that genes are selectively inactivated in the myocardium at predetermined times38 rather than during embryogenesis, may be required to obviate undesired compensatory changes.
Several independent signals have been implicated in the activation of
the hypertrophic response, depending on the animal model used. Many of
these agonists couple to phospholipase C, protein kinase C, and
downstream effectors, such as the NHE, via the GTPase-activating
protein Gq. When pressure overload was induced in transgenic mice
lacking functional Gq, these mice developed significantly less
ventricular hypertrophy than control
animals.39 However, the inability of the Gq
knockout to completely abolish the ventricular
hypertrophy indicates that other pathways (eg, tyrosine
kinase–coupled receptors, cytokines, other G proteins,
mechanical force) were important. Sakata et al40
demonstrated that overexpression of Gq in the myocardium
produced a pattern of gene expression similar to the known
characteristics of nontransgenic pressure-overloaded mice. However, in
this latter transgenic model, the effect of Gq overexpression, plus
aortic banding, resulted in a maladaptive form of
hypertrophy with cardiac decompensation. Taken together,
results from these 2 transgenic studies suggest that cardiac growth and
the severity of the hypertrophy are highly dependent on the
interaction of mechanical forces, with a diverse number of autocrine,
paracrine, and/or endocrine factors.
It is clear that not all types of cardiac hypertrophy use the same stimuli to mediate growth responses. Depending on the circumstances, one factor may be predominant, whereas in another setting, synergism among factors may be required to orchestrate the hypertrophic response. Under conditions of severe pressure overload, as with ascending aorta constriction, mechanical force may be the predominant stimulus. For example, in rats with severe aortic stenosis, long-term administration of the specific AT1 receptor antagonists improved left ventricular diastolic function but failed to regress left ventricular hypertrophy.41 A similar effect may be observed when the right ventricle is overloaded by constriction of the pulmonary artery.42 In these animal models, Ang II effects were clearly secondary to mechanical effects on the ventricle. It remains to be determined whether these and other acute animal models can be used to elucidate growth mechanisms in human cardiac hypertrophy, which is a very slow process, often developing over several years.
Conclusion
Several peptide factors and cytokines that affect cardiac function and induce hypertrophic growth have been shown to be synthesized and released from cardiac myocytes. The ability of AT1 receptor antagonists to block stretch-induced hypertrophic responses argues strongly for a role of Ang II in certain aspects of mechanically induced growth. However, it is apparent that in the pressure-overloaded heart, several local factors may work in synergistic and opposing fashions to regulate cardiac function. Thus, complex reciprocal relationships exist between individual mediators, which affect both release and actions. Although most studies have focused on the acute production and influence of these factors on cardiac function, longer-term modulation of cardiac structure and function is likely to be equally or more important. The sequence of events responsible for Ang II– and ET-1–induced activation of the NHE and cardiac hypertrophy remains unknown. Identification of the mechanotransducer, study of the synthesis and processing pathways for Ang II and ET-1, and interdigitation of the signaling pathways evoked by these 2 agents remain important areas to be investigated.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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