© 2001 American Heart Association, Inc.
Editorial |
Stimulating G Protein–Coupled Receptors
Cure or Cause for Heart Failure?
From the Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, and Hackensack University Medical Center, Hackensack, NJ.
Correspondence to Dorothy E. Vatner, MD, Cardiovascular Research Institute, The Jurist Research Building, Hackensack University Medical Center, 30 Prospect Ave, Hackensack, NJ 07601. E-mail dvatner{at}humed.com
Key Words: heart failure • ß-adrenergic receptors • vasopressin 2 receptors
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Introduction |
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 Top Introduction References |
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Historically there has been intense interest in restoring to the failing heart the ability to improve contractility to normal levels. This concept, which has been pursued with almost religious zeal for the last half century, is based on the intuitive assumption that the defect in heart failure resides at the end point, which is defective myocyte contraction.
This concept was given additional impetus by the observation by Chidsey et al1 that failing human hearts exhibit norepinephrine depletion. Over the last half century, the pharmaceutical industry has responded to this concept with a variety of ß-adrenergic agonists designed to improve the contractility of the failing heart. For several years, isoproterenol was administered, which provided some short-term relief but was found to exert deleterious effects in most patients. Most likely, the isoproterenol-induced increases in cardiac rate, contractility, and oxygen consumption are maladaptive in patients with limited coronary reserve. This was followed by a series of ß1-predominant or ß1-selective agonists that induce enhanced contractility with little or no effect on heart rate or arterial pressure. Some of these agents were used for many years in clinical setting as well as under experimental conditions. It was not until carefully controlled long-term studies were carried out that it was found that mortality was increased in patients with heart failure on these drugs.2 3 4 The results of these studies suggest that agents that increase oxygen consumption over an extended period of time may not be salutary in patients with limited coronary reserve.
During the last 20 years, heart failure research has uncovered another major problem governing the efficacy of catecholamine stimulation of contractility, ie, the desensitization that occurs in patients and experimental animals with chronic heart failure.5 6 This presents another challenge to developing a therapy that is based on stimulating ß-adrenergic receptors or increasing cAMP, ie, that downregulation of ß-adrenergic receptors or even the catalytic unit of adenylyl cyclase may rapidly limit the usefulness of long-term therapy.
The study by Laugwitz et al7 in this issue of the Circulation Research proposes a potentially novel approach to the issue of replacement inotropic therapy in heart failure. These authors tested the hypothesis that heterotrimeric GTP-binding protein (G protein)–coupled receptors other than the ß-adrenergic receptor might be resistant to desensitization and potentially useful in the treatment of heart failure. They examined the effects of transfected V2 vasopressin receptors (rV2 receptors) and P1 parathyroid hormone (PTH) and PTH-related peptide (rPTH1) receptors, which are not normally expressed in ventricular myocytes, on isolated ventricular myocytes from rabbits with and without rapid ventricular pacing–induced heart failure. Isolated adult myocytes were treated using recombinant adenoviral gene transfer of three different genes (rV2 receptors, rPTH1 receptors, and ß2-adrenergic receptors). Basal contractility in myocytes with transfected rPTH1 receptors and ß2-adrenergic receptors was found to be constitutively activated and could not be additionally stimulated with specific agonists. In myocytes transfected with rV2 receptors, basal contractility was similar to control levels in untransfected myocytes, and contractility increased with V2 receptor agonist exposure and was additionally stimulated with isoproterenol via cAMP production.
The hypothesis proposed in the study by Laugwitz et al7 is that overexpressing a non–ß-adrenergic G protein–coupled receptor in failing ventricular myocytes will ultimately improve myocardial function. The conclusion that transfection of rV2 receptors in cardiac myocytes may provide a useful long-term treatment for the failing heart is intriguing but remains clouded by several concerns. It is obvious that expression of rV2 receptors in these studies provides some improvement in contractility in failing myocytes when an rV2 receptor agonist is combined with isoproterenol stimulation. However, if rV2 receptors work through cAMP, then desensitization in the failing heart should still be an eventual outcome that will limit the utility of this therapy. Indeed, the catalytic unit of adenylyl cyclase was reported to be impaired in the failing heart,8 and proximal stimulation by rV2 receptors will not overcome a defect at a more distal site.
Thus, the most important questions remain unanswered in this study; ie, what are the long-term consequences of stimulating contraction through transfected V2 vasopressin receptors in heart failure? In view of the well-established concerns related to the problems of increasing oxygen consumption in the face of limited coronary reserve and the problems of desensitization, this critical question needs to be examined.
A first step in identifying potential long-term
consequences of transfecting V2 receptors could
be accomplished in vitro. By applying appropriate agonists, it could be
determined if the transfected V2 receptors
predisposed myocytes to hypertrophy or apoptosis.
An additional approach to addressing these concerns is to develop a
transgenic animal model. This would provide long-term stimulation of
V2 receptors, and it would be apparent if
desensitization occurred. Several transgenic animals have been
developed to examine overexpression of ß-adrenergic signaling. Both
ß1-adrenergic
receptors9 and
ß2-adrenergic
receptors10 have been
overexpressed as well as the G protein
Gs
.11 12 Of
these models, only mice with ß1-adrenergic
overexpression develop cardiomyopathy
rapidly.9 Overexpression of
Gs requires more than 1 year for cardiomyopathy
to develop.11 12
Overexpression of ß2-adrenergic receptors also
causes cardiomyopathy, given enough
time.13 Despite these
studies with pathological results, work is still progressing on
chronically enhancing inotropy as a treatment for heart failure in
genetically engineered animals. There is still hope that expressing
ß2-adrenergic receptors at a very low level or
inhibiting ß-adrenergic receptor
kinase14 15 may
prove useful. The present study using overexpression of
V2 receptors may also ultimately prove to be
useful. However, without more in vitro work and long-term studies in
normal animals or, better yet, in models of heart failure, it is too
premature to tell.
One final caveat requires mentioning. It may not be
the long-term elevation of contractility and oxygen
demand that is responsible for the deleterious action of G
protein–coupled receptor activation under chronic conditions. It may
be that distal signaling pathways are equally responsible for the
hypertrophy, apoptosis, necrosis, and development
of fibrosis that occurs in the long-term setting of overexpression of
these receptors. For example, different signaling pathways stimulating
extracellular signal–regulated kinase, mitogen-activated
protein kinase, phospholipase C, or calcineurin pathways may be
responsible for these negative effects independent of their action to
increase contractility in vivo. In this connection,
using a chimeric model where islands of overexpressed Gs cells were
mixed in a sea of nontransgenic myocytes, there was progression to
hypertrophy and fibrosis, even in hearts with limited
alterations in global left ventricular
function.16
In conclusion, the study by Laugwitz et al7 has provided a potentially novel approach to heart failure treatment. However, it is important to understand what this treatment will do to myocardial oxygen consumption when V2 receptors are chronically stimulated and to desensitization of their action at the level of the receptor cAMP or on more distal mechanisms. Although the data in the present study demonstrate an acute efficacy,7 the critical question is whether the addition of V2 vasopressin receptors in the cardiac myocyte will alleviate or exacerbate the progression of heart failure.
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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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TopIntroductionReferences |
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1. Chidsey CA, Braunwald E, Morrow AG. Catecholamine excretion and cardiac stores of norepinephrine in congestive heart failure. Am J Med. 1965;39:442–445.[Medline] [Order article via Infotrieve]
2. Krell MJ, Kline EM, Bates ER, Hodgson JM, Dilworth LR, Laufer N, Vogel RA, Pitt B. Intermittent, ambulatory dobutamine infusions in patients with severe congestive heart failure. Am Heart J. 1986;112:787–791.[Medline] [Order article via Infotrieve]
3. The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet. 1990;336:1–6.[Medline] [Order article via Infotrieve]
4. O’Connor CM, Gattis WA, Uretsky BF, Adams KF JR, McNulty SE, Grossman SH, McKenna WJ, Zannad F, Swedberg K, Gheorghiade M, Califf RM. Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1999;138:78–86.[Medline] [Order article via Infotrieve]
5. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB. Decreased catecholamine sensitivity and ß-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982;307:205–211.[Abstract]
6. Kiuchi K, Shannon RP, Komamura K, Cohen DJ, Bianchi C, Homcy CJ, Vatner SF, Vatner DE. Myocardial ß-adrenergic receptor function during the development of pacing-induced heart failure. J Clin Invest. 1993;91:907–914.
7.
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K-L, Weig H-J, Moretti A, Hoffmann E, Ueblacker P, Pragst I, Rosport K,
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