Douglas G Tilley1, Weizhong Zhu2, Valerie D Myers2, Larry A Barr2, Erhe Gao2, Xue Li2, Jianliang Song2, Rhonda L Carter2, Catherine A Makarewich2, Daohai Yu2, Constantine D Troupes2, Laurel A Grisanti2, Ryan C Coleman2, Walter J Koch2, Steven R Houser2, Joseph Y Cheung2, Arthur M Feldman2. 1. From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.). douglas.tilley@temple.edu arthur.feldman@tuhs.temple.edu. 2. From the Center for Translational Medicine (D.G.T., E.G., J.S, R.L.C., L.A.G., W.J.K., J.Y.C.), Department of Pharmacology (D.G.T., W.J.K.), Cardiovascular Research Center (W.Z., V.D.M., L.A.B., C.A.M., C.D.T., R.C.C., S.R.H.), Department of Physiology (L.A.B., C.A.M., S.R.H., A.M.F.), Department of Clinical Sciences (D.Y.), and Department of Medicine (J.Y.C., A.M.F.), Temple University School of Medicine, Philadelphia, PA; and the Division of Cardiology, Fourth Military Medical University, Xian, People's Republic of China (X.L.).
Abstract
BACKGROUND: Enhanced arginine vasopressin levels are associated with increased mortality during end-stage human heart failure, and cardiac arginine vasopressin type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulates βAR responsiveness and in doing so contributes to development of heart failure. METHODS AND RESULTS: Transaortic constriction resulted in decreased cardiac function and βAR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased βAR ligand affinity, as well as βAR-induced Ca(2+) mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of βAR responsiveness was demonstrated to occur in a previously unrecognized Gq protein-independent/G protein receptor kinase-dependent manner. CONCLUSIONS: This newly discovered relationship between cardiac V1AR and βAR may be informative for the treatment of patients with acute decompensated heart failure and elevated arginine vasopressin.
BACKGROUND: Enhanced arginine vasopressin levels are associated with increased mortality during end-stage humanheart failure, and cardiac arginine vasopressin type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulates βAR responsiveness and in doing so contributes to development of heart failure. METHODS AND RESULTS: Transaortic constriction resulted in decreased cardiac function and βAR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased βAR ligand affinity, as well as βAR-induced Ca(2+) mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of βAR responsiveness was demonstrated to occur in a previously unrecognized Gq protein-independent/G protein receptor kinase-dependent manner. CONCLUSIONS: This newly discovered relationship between cardiac V1AR and βAR may be informative for the treatment of patients with acute decompensated heart failure and elevated arginine vasopressin.
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