Appraisal of the Role of Angiotensin II and Aldosterone in Ventricular Myocyte Apoptosis in Adult Normotensive Rat

N. de Angelis, F. Fiordaliso, R. Latini, M. Gobbi, T. Mennini and S. Masson. Appraisal of the Role of Angiotensin II and Aldosterone in Ventricular Myocyte Apoptosis in Adult Normotensive Rat. Journal of Molecular and Cellular Cardiology (2002) 34, 1655–1665. Despite previous observations on isolated ventricular myocytes, there are still few evidences that angiotensin II induces cardiomyocyte apoptosis in vivo. The possibility that aldosterone, the final hormone of the renin-angiotensin-aldosterone system under Ang II control, can stimulate cardiac apoptosis has not yet been explored. Angiotensin II or aldosterone (1 mg/kg each) were infused in adult normotensive rats for different times, and the number of apoptotic ventricular myocyte nuclei was quantified by the TUNEL method, along with caspase-3 activation. The role of angiotensin II type 1 receptor in vivo was assessed by selective blockade with valsartan and ex vivo by binding experiments. In addition, myocytes in primary culture were incubated with Ang II or aldosterone in presence of spironolactone. Continuous infusion of Ang II induced a rapid, AT1-mediated increase of apoptotic cardiomyocyte nuclei (from 14±9 to 188±35 TdT-labeled nuclei/106 after 3 h, P<0.005) and of activated caspase-3, that normalized after 24 h. The normalization was associated with a down-regulation of myocardial AT1 receptors. Aldosterone stimulated cardiomyocyte apoptosis both in vivo and in isolated cells, to a similar extent as Ang II. The maximal apoptotic rate reported here (~0.02%) and the transient effect of Ang II suggest that myocyte loss by apoptosis is limited in the present model. The data on aldosterone-induced ventricular myocyte apoptosis deserve further attention to delineate the role of aldosterone in cell death and offer possible mechanistic explanations on the benefits afforded by aldosterone receptor antagonists in heart failure.