FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2156988690> ?p ?o ?g. }

• W2156988690 endingPage "647" @default.
• W2156988690 startingPage "645" @default.
• W2156988690 abstract "HomeCirculation ResearchVol. 88, No. 7Stimulating G Protein–Coupled Receptors Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBStimulating G Protein–Coupled Receptors Cure or Cause for Heart Failure? Dorothy E. Vatner Dorothy E. VatnerDorothy E. Vatner 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. Search for more papers by this author Originally published13 Apr 2001https://doi.org/10.1161/hh0701.089951Circulation Research. 2001;88:645–647Historically 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 β-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 β1-predominant or β1-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.234 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.56 This presents another challenge to developing a therapy that is based on stimulating β-adrenergic receptors or increasing cAMP, ie, that downregulation of β-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 β-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 β2-adrenergic receptors). Basal contractility in myocytes with transfected rPTH1 receptors and β2-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–β-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 β-adrenergic signaling. Both β1-adrenergic receptors9 and β2-adrenergic receptors10 have been overexpressed as well as the G protein Gsα.1112 Of these models, only mice with β1-adrenergic overexpression develop cardiomyopathy rapidly.9 Overexpression of Gsα requires more than 1 year for cardiomyopathy to develop.1112 Overexpression of β2-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 β2-adrenergic receptors at a very low level or inhibiting β-adrenergic receptor kinase1415 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 Gsα 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.16In 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.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Dorothy E. Vatner, MD, Cardiovascular Research Institute, The Jurist Research Building, Hackensack University Medical Center, 30 Prospect Ave, Hackensack, NJ 07601. E-mail [email protected] References 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.CrossrefMedlineGoogle Scholar2 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.CrossrefMedlineGoogle Scholar3 The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet.1990; 336:1–6.CrossrefMedlineGoogle Scholar4 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.CrossrefMedlineGoogle Scholar5 Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB. Decreased catecholamine sensitivity and β-adrenergic-receptor density in failing human hearts. N Engl J Med.1982; 307:205–211.CrossrefMedlineGoogle Scholar6 Kiuchi K, Shannon RP, Komamura K, Cohen DJ, Bianchi C, Homcy CJ, Vatner SF, Vatner DE. Myocardial β-adrenergic receptor function during the development of pacing-induced heart failure. J Clin Invest.1993; 91:907–914.CrossrefMedlineGoogle Scholar7 Laugwitz K-L, Weig H-J, Moretti A, Hoffmann E, Ueblacker P, Pragst I, Rosport K, Schömig A, Ungerer M. Gene transfer of heterologous G protein–coupled receptors to cardiomyocytes: differential effects on contractility. Circ Res.2001; 88:688–695.CrossrefMedlineGoogle Scholar8 Ishikawa Y, Sorota S, Kiuchi K, Shannon RP, Komamura K, Katsushika S, Vatner DE, Vatner SF, Homcy CJ. Downregulation of adenylyl cyclase types V and VI mRNA levels in pacing-induced heart failure in dogs. J Clin Invest.1994; 93:2224–2229.CrossrefMedlineGoogle Scholar9 Engelhardt S, Hein L, Wiesmann F, Lohse MJ. Progressive hypertrophy and heart failure in β1-adrenergic receptor transgenic mice. Proc Natl Acad Sci U S A.1999; 96:7059–7064.CrossrefMedlineGoogle Scholar10 Milano CA, Allen LF, Rockman HA, Dolber PC, McMinn TR, Chien KR, Johnson TD, Bond RA, Lefkowitz RJ. Enhanced myocardial function in transgenic mice overexpressing the β2-adrenergic receptor. Science.1994; 264:582–586.CrossrefMedlineGoogle Scholar11 Iwase M, Bishop SP, Uechi M, Vatner DE, Shannon RP, Kudej RK, Wight DC, Wagner TE, Ishikawa Y, Homcy CJ, Vatner SF. Adverse effects of chronic endogenous sympathetic drive induced by cardiac Gsα overexpression. Circ Res.1996; 78:517–524.CrossrefMedlineGoogle Scholar12 Iwase M, Uechi M, Vatner DE, Asai K, Shannon RP, Kudej RK, Wagner TE, Wight DC, Patrick TA, Ishikawa Y, Homcy CJ, Vatner SF. Cardiomyopathy induced by cardiac Gsα overexpression. Am J Physiol.1997; 272:H585–H589.MedlineGoogle Scholar13 Dorn GW II, Tepe NM, Lorenz JN, Koch WJ, Liggett SB. Low- and high-level transgenic expression of β2-adrenergic receptors differentially affect cardiac hypertrophy and function in Gαq-overexpressing mice. Proc Natl Acad Sci U S A.1999; 96:6400–6405.CrossrefMedlineGoogle Scholar14 Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA, Lefkowitz RJ. Cardiac function in mice overexpressing the β-adrenergic receptor kinase or a β ARK inhibitor. Science.1995; 268:1350–1353.CrossrefMedlineGoogle Scholar15 Rockman HA, Chien KR, Choi D-J, Iaccarino G, Hunter JJ, et al. Expression of a β-adrenergic receptor kinase 1 inhibitor prevents the development of heart failure in gene-targeted mice. Proc Natl Acad Sci U S A.1998; 95:7000–7005.CrossrefMedlineGoogle Scholar16 Vatner DE, Yang G-P, Geng YJ, Asai K, Yun JS, Wagner TE, Ishikawa Y, Bishop SP, Homcy CJ. Determinants of the cardiomyopathic phenotype in chimeric mice overexpressing cardiac Gsα. Circ Res.2000; 86:802–806.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails April 13, 2001Vol 88, Issue 7 Advertisement Article InformationMetrics © 2001 American Heart Association, Inc.https://doi.org/10.1161/hh0701.089951 Originally publishedApril 13, 2001 Keywordsvasopressin 2 receptorsβ-adrenergic receptorsheart failurePDF download Advertisement" @default.
• W2156988690 created "2016-06-24" @default.
• W2156988690 creator A5056890673 @default.
• W2156988690 date "2001-04-13" @default.
• W2156988690 modified "2023-09-25" @default.
• W2156988690 title "Stimulating G Protein–Coupled Receptors" @default.
• W2156988690 cites W1965980675 @default.
• W2156988690 cites W1976677443 @default.
• W2156988690 cites W1977584503 @default.
• W2156988690 cites W1983902487 @default.
• W2156988690 cites W1989282030 @default.
• W2156988690 cites W2023929054 @default.
• W2156988690 cites W2043698693 @default.
• W2156988690 cites W2071092788 @default.
• W2156988690 cites W2077425788 @default.
• W2156988690 cites W2124114189 @default.
• W2156988690 cites W2158800467 @default.
• W2156988690 cites W4210834519 @default.
• W2156988690 doi "https://doi.org/10.1161/hh0701.089951" @default.
• W2156988690 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/11304483" @default.
• W2156988690 hasPublicationYear "2001" @default.
• W2156988690 type Work @default.
• W2156988690 sameAs 2156988690 @default.
• W2156988690 citedByCount "1" @default.
• W2156988690 crossrefType "journal-article" @default.
• W2156988690 hasAuthorship W2156988690A5056890673 @default.
• W2156988690 hasBestOaLocation W21569886901 @default.
• W2156988690 hasConcept C135285700 @default.
• W2156988690 hasConcept C170493617 @default.
• W2156988690 hasConcept C185592680 @default.
• W2156988690 hasConcept C55493867 @default.
• W2156988690 hasConcept C86803240 @default.
• W2156988690 hasConcept C95444343 @default.
• W2156988690 hasConceptScore W2156988690C135285700 @default.
• W2156988690 hasConceptScore W2156988690C170493617 @default.
• W2156988690 hasConceptScore W2156988690C185592680 @default.
• W2156988690 hasConceptScore W2156988690C55493867 @default.
• W2156988690 hasConceptScore W2156988690C86803240 @default.
• W2156988690 hasConceptScore W2156988690C95444343 @default.
• W2156988690 hasIssue "7" @default.
• W2156988690 hasLocation W21569886901 @default.
• W2156988690 hasLocation W21569886902 @default.
• W2156988690 hasOpenAccess W2156988690 @default.
• W2156988690 hasPrimaryLocation W21569886901 @default.
• W2156988690 hasRelatedWork W1498784784 @default.
• W2156988690 hasRelatedWork W1967231335 @default.
• W2156988690 hasRelatedWork W1970046535 @default.
• W2156988690 hasRelatedWork W2002309357 @default.
• W2156988690 hasRelatedWork W2031950886 @default.
• W2156988690 hasRelatedWork W2035184614 @default.
• W2156988690 hasRelatedWork W2063998199 @default.
• W2156988690 hasRelatedWork W2137038958 @default.
• W2156988690 hasRelatedWork W2270573517 @default.
• W2156988690 hasRelatedWork W2802460976 @default.
• W2156988690 hasVolume "88" @default.
• W2156988690 isParatext "false" @default.
• W2156988690 isRetracted "false" @default.
• W2156988690 magId "2156988690" @default.
• W2156988690 workType "article" @default.