This Article Full Text Full Text (PDF) Data Supplement Data Supplement All Versions of this Article: 46/2/426    most recent 01.HYP.0000173069.53699.d9v1 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 PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Domenighetti, A. A. Articles by Delbridge, L. M.D. Search for Related Content PubMed PubMed Citation Articles by Domenighetti, A. A. Articles by Delbridge, L. M.D. Related Collections Contractile function Remodeling Hypertrophy

(Hypertension. 2005;46:426.)
© 2005 American Heart Association, Inc.

Original Articles

Angiotensin II–Mediated Phenotypic Cardiomyocyte Remodeling Leads to Age-Dependent Cardiac Dysfunction and Failure

Andrea A. Domenighetti; Qing Wang; Marcel Egger; Stephen M. Richards; Thierry Pedrazzini; Lea M.D. Delbridge

From the Department of Physiology (A.A.D., L.M.D.D.), University of Melbourne, Australia; the Department of Medicine (Q.W., T.P.), University of Lausanne Medical School, Switzerland; the Department of Physiology (M.E.), University of Bern, Switzerland; and the Division of Biochemistry (S.M.R.), University of Tasmania, Australia.

Correspondence to Dr Lea M. Durham Delbridge, PhD, Department of Physiology, University of Melbourne, Parkville Victoria, 3010, Australia. E-mail lmd{at}unimelb.edu.au

Chronic elevation of plasma angiotensin II (Ang II) is detrimental to the heart. In addition to its hemodynamic effects, Ang II exerts cardiotrophic actions that contribute to cardiomyocyte remodeling. However, it remains to be clarified whether these direct actions of Ang II are sufficient to cause contractile dysfunction and heart failure in the absence of altered hemodynamic conditions. In this study, we used TG1306/1R (TG) mice that develop Ang II–mediated cardiac hypertrophy in absence of elevated blood pressure to investigate the phenotypic changes in cardiomyocytes during the adaptive response to chronic cardiac-specific endogenous Ang II stimulation. A 94-week longitudinal study demonstrated that TG mice develop dilated cardiomyopathy with aging and exhibit a significant increase in mortality compared with wild-type (WT) mice. Cardiac hypertrophy in TG mice is associated with cardiomyocyte hypertrophy (15 to 20 weeks: length +20%; 35 to 40 weeks: length +10%, width +15%) but not collagen deposition. In vivo analysis of cardiac function revealed age-dependent systolic and diastolic dysfunction in TG mice (45% reduction in dP/dt_max and dP/dt_min at 50 to 60 weeks of age compared with WT). Analysis of isolated cardiomyocyte isotonic shortening showed impaired contractility in TG cardiomyocytes (30% to 40% decrease in rates of shortening and lengthening). In TG hearts, chronic Ang II exposure induced downregulation of the sarcoplasmic reticulum calcium pump (SERCA2) and diminution of Ca²⁺ transients, indicative of an underlying disturbance in calcium homeostasis. In conclusion, chronic Ang II myocardial stimulation without hemodynamic overload is sufficient to produce cardiomyocyte and cardiac dysfunction culminating in heart failure.

Key Words: aging • cardiac function • heart failure • hypertrophy • myocytes • renin-angiotensin system

This article has been cited by other articles:

				K. Gusev, A. A. Domenighetti, L. M.D. Delbridge, T. Pedrazzini, E. Niggli, and M. Egger Angiotensin II-Mediated Adaptive and Maladaptive Remodeling of Cardiomyocyte Excitation-Contraction Coupling Circ. Res., July 2, 2009; 105(1): 42 - 50. [Abstract] [Full Text] [PDF]

				D.-F. Dai, L. F. Santana, M. Vermulst, D. M. Tomazela, M. J. Emond, M. J. MacCoss, K. Gollahon, G. M. Martin, L. A. Loeb, W. C. Ladiges, et al. Overexpression of Catalase Targeted to Mitochondria Attenuates Murine Cardiac Aging Circulation, June 2, 2009; 119(21): 2789 - 2797. [Abstract] [Full Text] [PDF]

				E. R. Porrello, A. D'Amore, C. L. Curl, A. M. Allen, S. B. Harrap, W. G. Thomas, and L. M.D. Delbridge Angiotensin II Type 2 Receptor Antagonizes Angiotensin II Type 1 Receptor-Mediated Cardiomyocyte Autophagy Hypertension, June 1, 2009; 53(6): 1032 - 1040. [Abstract] [Full Text] [PDF]

				C. E. Huggins, C. L. Curl, R. Patel, P. L. McLennan, M. L. Theiss, T. Pedrazzini, S. Pepe, and L. M. D. Delbridge Dietary fish oil is antihypertrophic but does not enhance postischemic myocardial function in female mice Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H957 - H966. [Abstract] [Full Text] [PDF]

				A. Croquelois, A. A. Domenighetti, M. Nemir, M. Lepore, N. Rosenblatt-Velin, F. Radtke, and T. Pedrazzini Control of the adaptive response of the heart to stress via the Notch1 receptor pathway J. Exp. Med., December 22, 2008; 205(13): 3173 - 3185. [Abstract] [Full Text] [PDF]

				G. Zhou, X. Li, D. W. Hein, X. Xiang, J. P. Marshall, S. D. Prabhu, and L. Cai Metallothionein Suppresses Angiotensin II-Induced Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation, Nitrosative Stress, Apoptosis, and Pathological Remodeling in the Diabetic Heart J. Am. Coll. Cardiol., August 19, 2008; 52(8): 655 - 666. [Abstract] [Full Text] [PDF]

				O. W. van den Brink, L. M D. Delbridge, T. Pedrazzini, F. L Rosenfeldt, and S. Pepe Augmented myocardial methionine-enkephalin in a murine model of cardiac angiotensin II-overexpression Journal of Renin-Angiotensin-Aldosterone System, December 1, 2007; 8(4): 153 - 159. [Abstract] [PDF]

				T. L. Reudelhuber, K. E. Bernstein, and P. Delafontaine Is Angiotensin II a Direct Mediator of Left Ventricular Hypertrophy?: Time for Another Look Hypertension, June 1, 2007; 49(6): 1196 - 1201. [Full Text] [PDF]

				M. Paul, A. Poyan Mehr, and R. Kreutz Physiology of local Renin-Angiotensin systems. Physiol Rev, July 1, 2006; 86(3): 747 - 803. [Abstract] [Full Text] [PDF]