Abstract
The present study aimed to test whether angiotensin receptor blockers (ARBs) are cardioprotective after myocardial infarction (MI) by preventing augmented local renin-angiotensin-system (RAS)-induced oxidative stress injury and senescence, preserving resident stem cells, and restoring the insulin-like growth factor (IGF-1)/IGF-1 receptor (IGF-R) pathway. Sprague-Dawley rats with ligated or unligated coronary arteries were treated with losartan (20 mg/kg/d) or vehicle for 3 or 9 weeks. Heart function and molecular and histological changes were assessed. It was found MI induced left ventricular dysfunction and remodeling, increased levels of the oxidative stress marker 8-hydroxy-2'-deoxyguanosine and cell senescence marker p16ink4a, and downregulated the IGF-1/IGF-1R/Akt pathway after both 3 and 9 weeks post-MI. MI induced an increase in stem cells identified by immunostaining for c-kit and Wilms' tumor-1 predominantly after 3 weeks. Losartan significantly inhibited local cardiac RAS activation and improved left ventricular function and remodeling at both timepoints. Losartan also preserved c-kit- and Wilms' tumor-1-positive cells (particularly at 3 weeks), attenuated 8-hydroxy-2'-deoxyguanosine- and p16ink4a-positive cardiomyocytes, and restored the IGF-1/IGF-1R/Akt pathway at both 3 and 9 weeks. In conclusion, ARBs aided cardiac repair post-MI through short-term preservation of stem cells and persistent anti-oxidative stress and anti-senescence effects, partially by attenuating activation of cardiac RAS and restoring the local IGF-1/IGF-1R/Akt pathway.