Blockade of
angiotensin II type 1 receptor (AT1) signaling attenuates
heart failure following
myocardial infarction (MI), perhaps through reduction of
fibrosis in the noninfarcted myocardium. However, its specific effect on the
infarct tissue itself has not been fully clarified, which we examined in the present study. After MI induction in mice, treatment with the AT1 blocker
olmesartan, beginning on the 3rd day post-MI, significantly improved survival (94%) 4 wk post-MI, compared with saline (53%) and
hydralazine (73%).
Olmesartan-treated mice also showed significant attenuation of left ventricular dilatation and dysfunction, as well as significantly greater
infarct wall thickness, although the absolute size of the
infarct scar was unchanged. In addition, significantly greater numbers of nonmyocytes (mainly vascular cells and myofibroblasts) were present within the
infarct scar in
olmesartan-treated hearts. Ten days post-MI, apoptosis among granulation tissue cells was significantly suppressed in the
olmesartan-treated hearts, where expression of Fas, Bax,
procaspase-3, and Daxx and activation of
caspase-3, c-Jun NH(2)-terminal
kinase, and c-Jun were all significantly attenuated. By contrast, expression of
Fas ligand, Bcl-2, and Fas-associated death domain and activation of
caspase-8 were unaffected, suggesting
olmesartan exerts a negative regulatory effect on the alternate pathway downstream of
Fas receptor. In vitro,
olmesartan dose-dependently inhibited Fas-mediated apoptosis in granulation tissue-derived myofibroblasts. The present study proposes this antiapoptotic effect as another important mechanism for an AT1 blocker in improving post-MI
ventricular remodeling, as well as its antifibrotic effect, and also suggests a significant link between
renin-
angiotensin and Fas/
Fas ligand systems in postinfarction hearts.