HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 288/1/H317    most recent 00957.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Nakayama, M. Articles by Lorell, B. H. Search for Related Content PubMed PubMed Citation Articles by Nakayama, M. Articles by Lorell, B. H.

Chronic ventricular myocyte-specific overexpression of angiotensin II type 2 receptor results in intrinsic myocyte contractile dysfunction

¹Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; ²Department of Cell and Developmental Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina; and ³Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, Ohio

Submitted 13 October 2003 ; accepted in final form 10 September 2004

ANG II type 2 receptor (AT₂) is upregulated in failing hearts, but its effect on myocyte contractile function is not known. We measured fractional cell shortening and intracellular Ca²⁺ concentration transients in left ventricular myocytes derived from transgenic mice in which ventricle-specific expression of AT₂ was driven by the myosin light chain 2v promoter. Confocal microscopy studies confirmed upregulation of AT₂ in the ventricular myocytes and partial colocalization of AT₂ with AT₁. Three components of contractile performance were studied. First, baseline measurements (0.5 Hz, 1.5 mmol/l extracellular Ca²⁺ concentration, 25°C) and study of contractile reserve at faster pacing rates (1–5 Hz) revealed Ca²⁺-dependent contractile dysfunction in myocytes from AT₂ transgenic mice. Comparison of two transgenic lines suggested a dose-dependent relationship between magnitude of contractile dysfunction and level of AT₂ expression. Second, activity of the Na⁺/H⁺ exchanger, a dominant transporter that regulates beat-to-beat intracellular pH, was impaired in the transgenic myocytes. Third, the inotropic response to -adrenergic versus ANG II stimulation differed. Both lines showed impaired contractile response to -adrenergic stimulation. ANG II elicited an increase in contractility and intracellular Ca²⁺ in wild-type myocytes but caused a negative inotropic effect in myocytes from AT₂ transgenic mice. In contrast with -adrenergic response, the depressed response to ANG II was related to level of AT₂ overexpression. The depressed response to ANG II was also present in myocytes from young transgenic mice before development of heart failure. Thus chronic overexpression of AT₂ has the potential to cause Ca²⁺- and pH-dependent contractile dysfunction in ventricular myocytes, as well as loss of the inotropic response to ANG II.

contractility; calcium ion transients; pH

This article has been cited by other articles:

				X. Yan, A. J. T. Schuldt, R. L. Price, I. Amende, F.-F. Liu, K. Okoshi, K. K. L. Ho, A. J. Pope, T. K. Borg, B. H. Lorell, et al. Pressure overload-induced hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1274 - H1281. [Abstract] [Full Text] [PDF]

				S. E. Sawaya, Y. S. Rajawat, T. G. Rami, G. Szalai, R. L. Price, N. Sivasubramanian, D. L. Mann, and D. S. Khoury Downregulation of connexin40 and increased prevalence of atrial arrhythmias in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1561 - H1567. [Abstract] [Full Text] [PDF]

				M. H. Strauss and A. S. Hall Angiotensin Receptor Blockers May Increase Risk of Myocardial Infarction: Unraveling the ARB-MI Paradox Circulation, August 22, 2006; 114(8): 838 - 854. [Full Text] [PDF]