β-Arrestin-1 reduces acute myocardial infarction via promoting autophagy in cardiomyocytes

Background and purpose: β-Arrestins are key regulators of G protein–coupled receptor (GPCR) signaling. Through their function as scaffolding proteins, β-arrestins mediate a range of cellular signaling events. However, the role of β-arrestins during myocardial ischemia remains incompletely understood. In this study, we explored the regulatory effects of β-arrestin-1 on autophagy following myocardial infarction and sought to identify the underlying mechanism. Methods: Acute myocardial infarction was induced by permanent left anterior descending coronary artery ligation. Cardiac function was assessed using echocardiography. β-Arrestin-1, autophagy-related 5 (ATG5), and liver kinase B1 (LKB1) were overexpressed or knocked down using lentivirus-mediated transduction of the gene or short hairpin RNA (shRNA) in cultured primary cardiomyocytes. Oxygen-glucose deprivation (OGD) in cardiomyocytes was used to simulate cardiac ischemia in vitro . Autophagy and apoptosis were assessed by western blot, flow cytometry, and transmission electron microscopy. Cell survival and lactate dehydrogenase (LDH) release were evaluated using the respective kits. Results: β-Arrestin-1 knockout (KO) increased myocardial infarction size, an effect that was associated with decreased autophagy and deterioration of cardiac function. The overexpression of β-arrestin-1 significantly increased autophagy levels and decreased cell apoptosis in cardiomyocytes exposed to OGD, whereas the knockdown of β-arrestin-1 exerted the opposite effect. The protective effect of β-arrestin-1 overexpression was abrogated by ATG5 knockdown. β-Arrestin-1 KO attenuated the myocardial infarction–induced phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). In cultured myocytes, the blockade of AMPK or the knockdown of LKB1 inhibited the β-arrestin-1–induced increase in the LC3-II/LC3-I ratio and beclin 1 expression levels and attenuated β-arrestin-1–mediated cardioprotective effects. Conclusions: Collectively, our findings suggested that β-arrestin-1 promotes cardiomyocyte survival under ischemic conditions via the regulation of LKB1/AMPK-dependent autophagy. These findings may be helpful in designing novel therapeutic strategies for myocardial ischemia.