Effects of the novel angiotensin II receptor type i antagonist, fimasartan on myocardial ischemia/reperfusion injury

Background The aim of this study was to investigate the cardioprotective effect of fimasartan, a newly developed angiotensin II receptor type I blocker (ARB), against myocardial ischemia/reperfusion (I/R) injury and to identify the mechanism by which it reduces mitochondrial damage. Methods Fimasartan was administered intravenously to Sprague-Dawley rats (3 mg/kg), cardiomyocytes (50 μM), and H9c2 cells (50 μM) before ischemia or hypoxia. Myocardial infarction (MI), echocardiograms, DNA fragmentation, terminal deoxynucleotidyl transferase-mediated dUTP in situ nick-end labeling, immunoblotting, oxygen consumption, confocal microscopic appearance, and L-type Ca^{2 +} current (I_Ca,L) were then assessed. Results Fimasartan pretreatment remarkably reduced the rate of MI and improved cardiac performance well after I/R (n = 9/group). Fimasartan also reduced apoptotic cell death both in vivo and in hypoxia/reoxygenation (H/R)-treated H9c2 cells (n = 5 ~ 8/group). H/R-induced mitochondrial O₂^- production and collapse of membrane potential were markedly attenuated in fimasartan-treated cardiomyocytes (n = 4~6/group). Additionally, mitochondrial Ca^{2 +} overload during reoxygenation was suppressed by fimasartan (n = 4~6/group), and this was found to be possibly related to the inhibition of I_Ca,L and mitochondrial Ca^{2 +} uniporter. Furthermore, fimasartan pretreatment increased phosphorylations of Akt and glycogen synthase kinase-3β (n = 5~7/group), decreased pro-apoptotic p53 levels, and increased anti-apoptotic Bcl-2 levels (n = 4) during reperfusion. Conclusions Fimasartan preconditioning has the potential to modulate Bcl-2 and suppress I/R-induced Ca^{2 +} overload by inhibiting I_Ca,L and MCU. These beneficial effects could prevent the mitochondrial dysfunction and apoptosis accompanied by I/R.