Vaspin alleviates pathological cardiac hypertrophy by regulating autophagy-dependent myocardial senescence

Abstract

Abstract Background Visceral adipose tissue–derived serine protease inhibitor (vaspin), a secretory adipokine, protects against insulin resistance. Recent studies have demonstrated that serum vaspin levels are decreased in patients with coronary artery disease and that vaspin protects against myocardial ischemia-reperfusion injury and atherosclerosis. However, it remains unclear whether vaspin exerts specific effects on pathological cardiac hypertrophy. Methods An in vivo study was conducted using a cardiac hypertrophy model established by subcutaneous injection of isoproterenol (ISO) in C57BL/6 and vaspin-ko mice. Rapamycin was administered intraperitoneally to mice, for further study. H9c2 cells and neonatal rat ventricular myocytes (NRVMs) were treated with ISO to induce hypertrophy. Human vaspin fusion protein, the proteasome inhibitor MG132, and chloroquine diphosphate were used for further mechanistic studies. Results Here, we provide the first evidence that vaspin knockdown results in markedly exaggerated cardiac hypertrophy, fibrosis, and cardiomyocyte senescence in mice treated with ISO. Conversely, the administration of exogenous recombinant human vaspin protected NRVMs in vitro against ISO-induced hypertrophy and senescence. Furthermore, vaspin significantly potentiated the ISO-induced decrease in autophagy. Both rapamycin and chloroquine diphosphate regulated autophagy in vivo and in vitro, respectively, and participated in vaspin-mediated cardioprotection. Moreover, the PI3K-AKT-mTOR pathway plays a critical role in vaspin-mediated autophagy in cardiac tissues and NRVMs. Our data showed that vaspin downregulated the p85 and p110 subunits of PI3K by linking p85 and p110 to NEDD4L-mediated ubiquitination degradation. Conclusion Our results show, for the first time, that vaspin functions as a critical regulator that alleviates pathological cardiac hypertrophy by regulating autophagy-dependent myocardial senescence, providing potential preventive and therapeutic targets for pathological cardiac hypertrophy.