Abstract
Aliskiren is a direct renin inhibitor that has been effective in anti-hypertension. We investigated whether aliskiren could improve the ischemia-induced cardiac injury and whether the autophagy was involved in this effect. A myocardial infarction (MI) model was created by the ligation of the left anterior coronary artery in C57J/BL6 mice. They were treated for 1, 3, 7, and 14 days with vehicle or aliskiren (25 mg/kg/day via subcutaneous injection). In vivo, the MI mice exhibited worse cardiac function by echocardiographic assessment and showed larger myocardial scarring by light microscopy, whereas aliskiren treatment reversed these effects, which were also associated with the changes in caspase-3 and Bcl-2 expression as well as in the number of apoptotic cells. Aliskiren increased autophagy, as demonstrated by LC3B-II expression and transmission electron microscopy. Furthermore, H9c2 cardiomyocytes were employed as an in vitro model to examine the effects of aliskiren on apoptosis and autophagy under oxygen glucose deprivation (OGD)-induced injury. Aliskiren significantly increased cell viability in a dose-dependent manner. The beneficial effects of aliskiren were associated with decreased apoptosis and mitochondrial membrane potential as well as increased autophagy via increased autophagosome formation. We also found that aliskiren-induced cardiomyocyte survival occurred via AMP-activated protein kinase (AMPK)-dependent autophagy. Taken together, these results indicated that aliskiren increased cardiomyocyte survival through increased autophagosomal formation and decreased apoptosis and necrosis via modulating AMPK expression. AMPK-dependent autophagy may represent a novel mechanism for aliskiren in ischemic cardiac disease therapy.
Highlights
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide (Go et al, 2014)
In the first set of experiments, we investigated whether aliskiren improved cardiac function in myocardial infarction (MI) mice
The left ventricular (LV) wall thickness and LV wall area were dramatically decreased in a time-dependent manner; the reverse trend was observed with aliskiren treatment at 14 days (Table 2)
Summary
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide (Go et al, 2014). The role of autophagy remains unclear in CVD regarding whether the role of autophagy affects the cardiomyocytes from ischemia-induced death and drug treatment in vivo. Increased RAS activity results in the development of cardiac hypertrophy, apoptosis, and left ventricular (LV) dilatation, all known to contribute to increased morbidity and mortality in patients with postmyocardial infarction and heart failure. Prevention of this RAS activity, which depresses cardiac function after MI, remains an important pharmacological target in treating patients with MI. Aliskiren was shown to increase survival by decreasing apoptosis and increasing autophagy, improving the beneficial effect of cardiomyocytes on overall LV function in MI-treated mice. AMPK phosphorylation in oxygen glucose deprivation (OGD)treated cardiomyocytes, resulting in increased autophagy and attenuated apoptosis as well as subsequent increased cell viability
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