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(Circulation. 1996;93:1069-1072.)
© 1996 American Heart Association, Inc.
Articles |
Myocardial Endothelin
Does It Play a Role in Myocardial Failure?
From the Cardiomyopathy Program and Cardiovascular Divisions, Boston VA Medical Center and Boston University Medical Center, Boston University School of Medicine, Boston, Mass.
Correspondence to Wilson S. Colucci, MD, Cardiomyopathy Program, Boston University Medical Center, 88 E Newton St, Boston, MA 02118.
Key Words: hypertrophy • myocardium • heart failure • endothelin
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Introduction |
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 Top Introduction Cardiovascular Effects of...ET in Heart Failure...What Is the Mechanism...Is the Myocardial ET...Implications of the Myocardial...References |
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Endothelin (ET) is a 21–amino acid peptide that was initially identified in 1988 by Yanagisawa and colleagues1 as a potent vasoconstrictor substance elaborated by vascular endothelial cells. Several additional features have since become apparent. First, ET is a multifunctional peptide. In addition to causing contraction of arterial and venous smooth muscle, ET exerts pleiotropic effects on numerous aspects of cardiovascular, neuroendocrine, renal, gastrointestinal, and pulmonary function. Second, although endothelial cells are its major source, ET can be synthesized by numerous other cell types including cardiac myocytes, vascular smooth muscle cells, renal tubular epithelial cells, glomerular mesangial cells, glial cells, macrophages, mast cells, and pituitary cells. Third, ET has diverse effects on gene expression, indicating that in addition to its immediate effects on cellular function, ET may exert long-term effects on cellular growth and phenotype.
ET is synthesized as an
approximately 200–amino acid
prepro-hormone. Posttranslational cleavage yields a 38– to
39–amino acid pro-ET that undergoes an additional cleavage between
Trp21-Val22 to yield mature ET. The later
cleavage is mediated by one or more "ET converting enzymes," one
of which appears to be a metal-dependent neutral
endopeptidase. Three isoforms of ET, termed ET-1, ET-2,
and ET-3, have been identified, cloned, and sequenced. Two receptors
for ET, termed ETA and ETB, also have
been identified and shown to be expressed on several
cardiovascular cell types including
endothelial cells, vascular smooth muscle cells,
cardiac myocytes, and fibroblasts.2 The receptor subtypes
bind ET isoforms with different affinities: The ETA subtype
selectively binds ET-1=ET-2>ET-3, whereas the ETB subtype
shows no selectivity for the isoforms. ET receptors couple to numerous
second-messenger pathways. Like vasoconstrictors such as
angiotensin and 
-adrenergic agonists, ET has potent
effects on both Ca2+ signaling pathways and the hydrolysis
of phospholipids.2 In common with peptide growth factors,
ET can activate tyrosine kinases and
mitogen-activated protein kinase,3 signaling
pathways that regulate cellular growth.
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Cardiovascular Effects of Exogenous ET |
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TopIntroductionCardiovascular Effects of...ET in Heart Failure...What Is the Mechanism...Is the Myocardial ET...Implications of the Myocardial...References |
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In the vasculature, the predominant effect of ET is contraction as the result of direct stimulation of ETA receptors on vascular smooth muscle cells.2 In some vessels and species, stimulation of ETB receptors on endothelial cells may exert a counterregulatory vasodilator effect via release of prostacyclin and/or nitric oxide. However, in other settings the stimulation of ETB receptors may cause contraction. In addition to its immediate effects on vascular tone, long-term exposure to ET causes proliferation of vascular smooth muscle cells in vitro. Thus, like angiotensin and
-adrenergic agonists, ET may be involved in both the
short-term regulation of vascular tone and the long-term
modulation of vascular wall growth and remodeling. The myocardium expresses both ETA and ETB receptors, and in vitro observations have shown that exogenously applied ET is an extremely potent positive inotropic substance.4 5 This positive inotropic effect probably is not mediated by cAMP, since ET decreases the activity of adenylate cyclase. Rather, the positive inotropic effect of ET appears to be mediated, at least in part, by a protein kinase C–dependent alkalinization resulting in increased sensitivity of the myofilaments to calcium.5 ET exerts complex effects on heart rate, possibly reflecting opposing actions of the two ET receptor subtypes,6 and there is evidence that ET can slow diastolic relaxation of the myocardium.7
Despite the demonstrated effects of exogenous ET, it has not been clear whether endogenous ET plays a role in the physiological modulation of myocardial function. Increased levels of plasma ET have been observed in several cardiovascular conditions, including systemic hypertension, angina, cardiogenic shock, myocardial infarction, Raynaud's phenomenon, cerebral vasospasm, atherosclerosis, acute myocardial infarction, and heart failure. Although these observations have led to the suggestion that ET plays a pathophysiological role, or at the least is a disease marker, establishing a physiological or pathophysiological role for ET based on the response to exogenous ET is confounded by at least two limitations. First, the relevant concentration of the peptide is unknown. Although ET can be detected in the plasma of normal humans in concentrations ranging from 0.5 to 5 pmol/L, the observed dissociation constants for ET receptors range from 100 to 2000 pmol/L, suggesting that plasma ET would have to reach concentrations of approximately 10 pmol/L (and probably higher if protein binding is taken into consideration) to activate signaling pathways. It therefore seems likely that the actions of ET are most often mediated in an autocrine or paracrine manner by the much higher concentration of ET present in the tissues of origin. A second confounding factor is that the ET system in a given tissue may involve multiple cell types, ET isoforms, and ET receptor subtypes. For these reasons, it is difficult if not impossible to replicate the relevant cellular environment by the exogenous administration of ET. Several nonpeptide antagonists for ET receptors have been developed.2 8 Some of these are subtype-selective (eg, BQ-123 for the ETA receptor), whereas others are nonselective (eg, bosentan). In addition, an ET-converting enzyme has now been identified, and inhibitors are being developed. These antagonists have proved to be valuable in defining the role of the endogenous ET system and distinguishing the actions of the ET receptor subtypes.
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ET in Heart Failure |
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TopIntroductionCardiovascular Effects of...ET in Heart Failure...What Is the Mechanism...Is the Myocardial ET...Implications of the Myocardial...References |
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Several studies have demonstrated that plasma ET is elevated in patients with heart failure9 and in animal models of heart failure.10 Plasma ET was elevated in patients with mild heart failure (NYHA functional class I-II), and elevated further in patients with severe heart failure (NYHA III-IV). The increase in plasma ET does not appear to be related to the cause of heart failure (ischemic versus idiopathic) and does not correlate with serum urea or creatinine, suggesting that it is not caused by reduced renal clearance of the peptide. Cody et al9 found that in contrast to plasma norepinephrine and angiotensin, plasma ET does not correlate with several measures of hemodynamic function including cardiac index, stroke volume index, pulmonary artery wedge pressure, systemic arterial pressure, systemic vascular resistance, and heart rate. Interestingly, plasma ET correlated strongly with pulmonary artery pressures and pulmonary vascular resistance, leading to the suggestion that ET is an important mediator of reactive pulmonary hypertension in patients with heart failure.9
In this issue, Sakai et al11 use the nonpeptide ETA receptor–selective antagonist BQ-123 to examine the role of endogenous ET in modulating cardiac function in rats with heart failure after myocardial infarction. Several aspects of this study are noteworthy. First, they found that in normal rats, under basal conditions, BQ-123 had no apparent effect on cardiac function. This suggests that the ETA receptor does not play an important role in the physiological modulation of myocardial function. Second, it was found that in animals with left ventricular failure 3 weeks after a myocardial infarction, systemic infusion of BQ-123 decreased both myocardial contractility and heart rate, thus suggesting that in this pathological setting, ET contributed to the support of myocardial function. Third, it was found that in rats with infarctions the surviving myocardium expressed increased amounts of both ET and ET receptors. This latter finding provides a mechanism that might account for the selective effect of BQ-123 in the animals with myocardial failure.
These observations suggest that ET might help to support cardiac function in the setting of myocardial failure, and further that endogenous ET exerts its effect on myocyte function (at least in the rat) via the ETA receptor. This latter finding is consistent with the demonstration that the ETA receptor predominates by a ratio of 9:1 in normal rat myocardium. Since in this study myocardial ET receptor subtypes were not quantified in the animals after infarction, it remains to be seen which subtype of ET receptor is upregulated in failing myocardium. However, since the ETA subtype predominates in normal myocardium, it is unlikely that the increased dependence on ET in the failing myocardium is due solely to the relatively modest increase in ET receptor number (57%) that was observed but reflects the presumably more marked increase in endogenous ET production by the myocardium that is suggested by the >7-fold increase in prepro-ET mRNA.
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What Is the Mechanism by Which the Myocardial ET System Is Upregulated in Failing Myocardium? |
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TopIntroductionCardiovascular Effects of...ET in Heart Failure...What Is the Mechanism...Is the Myocardial ET...Implications of the Myocardial...References |
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There is evidence that the expression of myocardial ET is also induced in response to pressure12 or volume overload.13 This suggests that myocardial ET induction may be an early component of a generalized response to hemodynamic overload. It is not clear which cell type(s) is responsible for the increased expression of ET and ET receptors in failing myocardium, nor is it known which stimuli are responsible for upregulation of the ET system. There are several potential sources of ET in the myocardium, including large vessel and microvascular endothelial cells,14 endocardium,15 and myocytes.12 16 Several stimuli are known to induce ET expression in endothelial cells, including shear stress, hypoxia, transforming growth factor-ß, interleukin-1, tumor necrosis factor-
, and ET itself. In addition, there is
indirect evidence to suggest that the myocyte itself may be an
important source of ET in pathological conditions. Thus, it was shown
by in situ hybridization that prepro-ET mRNA is induced in myocytes of
rats with pressure overload–induced
hypertrophy.12 In cultured cardiac myocytes,
mechanical stretch can induce ET expression,17 further
providing a possible mechanism for the induction of ET in
myocardium that is subjected to increased mechanical
stresses. In addition, at least two other potent stimuli for ET
secretion in endothelial cells, transforming growth
factor-ß and tumor necrosis factor-, can be expressed in the
myocardium. Myocardial expression of transforming growth
factor-ß is increased by several hypertrophic stimuli including
hemodynamic overload and
norepinephrine.18 Tumor necrosis factor- is
expressed in failing human hearts,19 and in vitro its
synthesis is induced in myocardium exposed to mechanical
stretch.20 Finally, there is evidence that oxygen free
radicals can induce ET in the heart, apparently from the
endocardium.15 The increased expression of ET by failing myocardium is reminiscent of the increased myocardial expression in hypertrophied and failing myocardium of angiotensin, another potent vasoconstrictor peptide that exerts a positive inotropic effect. As with ET, the increased expression of angiotensin is associated with an increase in the expression of its receptor. The relationship between ET and angiotensin is noteworthy. In cultured cardiac myocytes, angiotensin II induces the expression of mRNA for the ETB receptor.21 In addition, the ability of angiotensin to cause cellular hypertrophy is abolished by the coadministration of an ET receptor antagonist or treatment of the cells with antisense RNA for ET,16 leading to the suggestion that the growth-promoting effect of angiotensin in cardiac myocytes is mediated by ET in an autocrine manner.
Teerlink et al22 observed that oral administration of the ET receptor antagonist bosentan caused similar reductions in mean arterial pressure in rats with heart failure after myocardial infarction and sham-operated rats despite an approximately 50% increase in plasma ET in the infarcted rats. Likewise, Sakai et al11 found that there was no increase in ET mRNA in the kidney from infarcted rats. These observations suggest that upregulation of the myocardial ET system with failure may be organ-specific. If this is the case, it would further support the view that myocardial ET is upregulated by local factors such as mechanical stress or locally produced peptides.
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Is the Myocardial ET Pathway Adaptive or Maladaptive in the Failing Heart? |
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TopIntroductionCardiovascular Effects of...ET in Heart Failure...What Is the Mechanism...Is the Myocardial ET...Implications of the Myocardial...References |
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Perhaps both. Clearly, upregulation of the ET pathway may be helpful in providing short-term inotropic support for the failing myocardium in which ß-adrenergic responsiveness is frequently attenuated. However, there is ample reason for concern that prolonged stimulation by an upregulated ET system may have important maladaptive effects on myocardial structure and function. First, like angiotensin and norepinephrine, ET induces hypertrophy and the expression of a fetal gene program in cultured cardiac myocytes.23 Such effects on myocyte phenotype might lead to the reduced expression of "adult" genes (eg, SR Ca2+ATPase) that are critical to normal myocardial function. Second, in cultured cardiac fibroblasts ET has important effects on collagen synthesis and degradation24 that could contribute to interstitial fibrosis, abnormal diastolic properties of the myocardium, and impaired delivery of oxygen and nutrients to myocytes. The relevance of these in vitro observations remains speculative. However, the demonstration that chronic administration of the ETA-selective antagonist BQ-123 prevented pressure overload–induced hypertrophy in the rat suggests that the ET pathway may contribute to myocardial hypertrophy in vivo.25
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Implications of the Myocardial ET System |
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TopIntroductionCardiovascular Effects of...ET in Heart Failure...What Is the Mechanism...Is the Myocardial ET...Implications of the Myocardial...References |
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These observations have implications both for understanding the basic mechanisms responsible for the myocardial response to mechanical overload and for the development of new treatments for myocardial failure. The demonstration that the myocardial ET system is upregulated in hypertrophied and failing myocardium and that ET can cause many of the features of myocardial remodeling that are associated with myocardial failure (eg, myocyte hypertrophy, interstitial fibrosis, and induction of a fetal pattern of gene expression) suggests that this signaling pathway could play a central role in the pathophysiology of myocardial failure. At present, it remains to be determined whether the myocardial ET system mediates (or modulates) remodeling of the myocardium in response to hemodynamic overload. If the myocardial ET system is found to be involved in myocardial remodeling, additional issues will be relevant. What is the role of ET vis-à-vis the growing number of peptide signaling pathways that can be activated in the myocardium by mechanical and humoral stimuli (eg, angiotensin, inflammatory cytokines, and peptide growth factors)? Is ET simply one of several peptides that act in concert, more or less in parallel, or does it occupy a particularly focal position as a distal convergence point for other pathways? Is activation of the myocardial ET system an early or late event in the response to hemodynamic overload? Which cells are responsible for the increased production of myocardial ET and ET receptors with mechanical overload? What are the relative roles of the isoforms of ET and the ET receptor subtypes in mediating various aspects of myocardial remodeling? Do the various inhibitors of the ET pathway (selective and nonselective ET receptor antagonists, ET converting enzyme inhibition) have comparable or differing effects on myocardial remodeling? The answers to these and other questions will add importantly to our understanding of the pathophysiology of myocardial remodeling and failure and ultimately will determine whether inhibition of the ET pathway proves to be an effective therapeutic intervention for preventing and ameliorating the development of myocardial failure in patients.
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Acknowledgments |
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This study was supported in part by grants R01-HL-42539 and P50-HL-52320 from the National Institutes of Health.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionCardiovascular Effects of...ET in Heart Failure...What Is the Mechanism...Is the Myocardial ET...Implications of the Myocardial...References |
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