Ischemic cardiomyopathy and the cellular renin-angiotensin system

Abstract

Background: Ischemic cardiomyopathy produced by non-occlusive coronary artery constriction is characterized by left ventricular failure and right ventricular dysfunction, but whether the local renin-angiotensin system (RAS) is implicated in myocyte dysfunction and cell death remains unclear.

Methods: Changes in single-cell mechanics, the localization of the various constituents of RAS in the myocardium, and the effects of angiotensin II (Ang II) stimulation on myocyte performance and cell death were measured.

Results: Chronic ischemia is coupled with alterations in the mechanical properties and calcium (Ca2+) transients of the remaining viable myocytes. The abnormalities in myocyte mechanics consist of depression in peak shortening and velocity of shortening. Moreover, peak systolic Ca2+ is significantly decreased in the cells. In vitro stimulation with Ang II ameliorates myocyte function and systolic Ca2+. Additionally, adult myocytes express genes for renin, angiotensinogen, angiotensin-converting enzyme (ACE), and Ang II receptors. Renin, ACE, and Ang II receptors mRNAs increase under the setting of impaired coronary perfusion. Similarly, the percentage of myocytes containing renin, Ang I, and Ang II increases as well. In vitro studies of neonatal and adult ventricular myocytes indicate that Ang II triggers programmed myocyte cell death and this phenomenon is mediated by activation of the AT1 receptor sub-type. Importantly, the AT1-receptor blocker, losartan, completely inhibits apoptosis.

Conclusions: These multiple observations are consistent with the notion that Ang II may exert 3 separate functions on the heart: (1) stimulation of myocyte hypertrophy, (2) amelioration of myocyte contractile performance, and (3) activation of the suicide program of myocytes.