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(Hypertension. 2009;53:1032.)
© 2009 American Heart Association, Inc.

Original Articles

Angiotensin II Type 2 Receptor Antagonizes Angiotensin II Type 1 Receptor–Mediated Cardiomyocyte Autophagy

Enzo R. Porrello; Angelo D'Amore; Claire L. Curl; Andrew M. Allen; Stephen B. Harrap; Walter G. Thomas; Lea M.D. Delbridge

From the Department of Physiology (E.R.P., C.L.C., A.M.A., S.B.H., L.M.D.D.), University of Melbourne, Victoria; Baker IDI Heart and Diabetes Institute (E.R.P., A.D., W.G.T.), Victoria; and the School of Biomedical Sciences (W.G.T.), University of Queensland, Queensland, Australia.

Correspondence to Lea M.D. Delbridge, Cardiac Phenomics Laboratory, Department of Physiology, University of Melbourne, Parkville, Victoria 3010, Australia. E-mail lmd{at}unimelb.edu.au

Autophagy has emerged as an important process in the pathogenesis of cardiovascular diseases, but the proximal triggers for autophagy are unknown. Angiotensin II plays a central role in the pathogenesis of cardiac hypertrophy and heart failure. In this study, we used angiotensin II type 1 (AT₁) and type 2 (AT₂) receptor–expressing adenoviruses in cultured neonatal cardiomyocytes to provide the first demonstration that neonatal cardiomyocyte autophagic activity is differentially modulated by AT₁ and AT₂ receptor subtypes. Angiotensin II stimulation (48 hours) of neonatal cardiomyocytes expressing the AT₁ receptor alone (Ad-AT₁; 10 multiplicities of infection) induced a significant increase in the number of HcRed-LC3 autophagosomes per cell (17.3±1.6 versus 33.3±4.1 autophagosomes per cell; P<0.05). Coexpression of a high ratio of AT₂:AT₁ (Ad-AT₂:Ad-AT₁ multiplicity of infection ratio: 20:5) receptors completely abrogated the AT₁-mediated increase in autophagy (9.3±1.4 versus 33.3±4.1 autophagosomes per cell; P<0.05). Treatment with the AT₂ receptor antagonist PD123319 did not reverse the AT₂-mediated antiautophagic effect. AT₁- and AT₂-mediated autophagic responses were also assessed in cardiomyocytes from a genetic model that exhibits neonatal myocardial growth suppression. In these neonate myocyte cultures, AT₁ receptor activation induced a marked increase in the number of myocytes containing cytoplasmic vacuoles compared with the control (22.7±4.1% versus 1.1±0.6%; P<0.001) and was characterized by a nonapoptotic autophagic phenotype. The incidence of cardiomyocyte autophagic vacuolization in this myocyte population decreased dramatically to only 0.4±0.2% in myocytes infected with a high ratio of Ad-AT₂:Ad-AT₁. This study provides the first description of reciprocal regulation of cardiomyocyte autophagic induction by the AT₁ and AT₂ receptor subtypes.

Key Words: angiotensin II • angiotensin II type 1 receptor • angiotensin II type 2 receptor • autophagy • hypertrophic heart rat • hypertrophy • neonate

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				U. M. Steckelings and T. Unger Angiotensin Receptors and Autophagy: Live and Let Die Hypertension, June 1, 2009; 53(6): 898 - 899. [Full Text] [PDF]