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

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.

Keywords

Autophagic flux / Myocardial senescence / Pathological cardiac hypertrophy / Ubiquitination / Vaspin

Conflict of interest statement

The authors declare no conflict of interest.

Author contributions

Yu H, Rui H, and Xue L participated in research design. Yu H, Rui H, and Zou D participated in the writing of the article. Yu H, Rui H, Chi K, and Xu P participated in the performance of the research. Yu H, Rui H, Liu L, and Song X contributed new reagents or analytic tools. Yu H, Rui H, Wu X, and Wang J participated in data analysis.

Funding

This study was supported by the State Key Program of the National Natural Science Foundation of China (82030059), National Natural Science Foundation of China (82172178, 82072144, 81873950, 81873953, 81300219, 81671951), National Key R&D Program of China (2020YFC1512700, 2020YFC1512705, 2020YFC1512703), National S&T Fundamental Resources Investigation Project (2018FY100600, 2018FY100602), Natural Science Foundation of Shandong Province (ZR2022MH078), Key R&D Program of Shandong Province (2019GSF108131), Taishan Pandeng Scholar Program of Shandong Province (tspd20181220), Taishan Young Scholar Program of Shandong Province (tsqn202103173, tsqn20161065, tsqn201812129), Youth Top-Talent Project of National Ten Thousand Talents Plan, and Qilu Young Scholar Program.

Ethical approval of studies and informed consent

This study was approved by the Ethics Committee of Qilu Hospital of Shandong University (KYLL-2022(ZM)-507, February 21, 2022).

Acknowledgments

None.

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