Ischemic cardiomyopathy and the cellular renin-angiotensin system

Background: Ischemic cardiomyopathy produced by non-occlusive coronary arte ry constriction is characterized by left ventricular failure and right vent ricular dysfunction, but whether the local renin-angiotensin system (RAS) i s 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 (A ng II) stimulation on myocyte performance and cell death were measured. Results: Chronic ischemia is coupled with alterations in the mechanical pro perties and calcium (Ca2+) transients of the remaining viable myocytes. The abnormalities in myocyte mechanics consist of depression in peak shortenin g and velocity of shortening. Moreover, peak systolic Ca2+ is significantly decreased in the cells. In vitro stimulation with Ang II ameliorates myocy te function and systolic Ca2+. Additionally, adult myocytes express genes f or renin, angiotensinogen, angiotensin-converting enzyme (ACE), and Ang II receptors. Renin, ACE, and Ang II receptors mRNAs increase under the settin g of impaired coronary perfusion. Similarly, the percentage of myocytes con taining renin, Ang I, and Ang II increases as well. In vitro studies of neo natal and adult ventricular myocytes indicate that Ang II triggers programm ed myocyte cell death and this phenomenon is mediated by activation of the AT(1) receptor sub-type. Importantly, the AT(1)-receptor blocker, losartan, completely inhibits apoptosis. Conclusions: These multiple observations are consistent with the notion tha t Ang II may exert 3 separate functions on the heart: (1) stimulation of my ocyte hypertrophy, (2) amelioration of myocyte contractile performance, and (3) activation of the suicide program of myocytes.