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

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.

MicroRNA-34c-5p provokes isoprenaline-induced cardiac hypertrophy by modulating autophagy via targeting ATG4B

Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34 c-5 p on cardiac hypertrophy and the mechanism involved. The expression of miR-34 c-5 p was proved to be elevated in heart tissues from isoprenaline(ISO)-infused mice. ISO also promoted miR-34 c-5 p level in primary cultures of neonatal rat cardiomyocytes(NRCMs). Transfection with miR-34 c-5 p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor(Anf) and β-myosin heavy chain(β-Mhc) in NRCMs. In contrast, treatment with miR-34 c-5 p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34 c-5 p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34 c-5 p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34 c-5 p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4 B(ATG4 B) was identified as a direct target of miR-34 c-5 p, and miR-34 c-5 p was certified to interact with 3’untranslated region of Atg4 b mRNA by dual-luciferase reporter assay. miR-34 c-5 p reduced the expression of ATG4 B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34 c-5 p abolished the detrimental effects of ISO by restoring ATG4 B and increasing autophagy. In conclusion, our findings illuminate that miR-34 c-5 p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4 B and autophagy. It suggests that regulation of miR-34 c-5 p may offer a new way for handling hypertrophy-related cardiac dysfunction.