Vaspin通过调节自噬依赖性心肌衰老来减轻病理性心肌肥大

Huaxiang Yu, Haiying Rui, Dan Zou, Kai Chi, Ping Xu, Xiaoshuai Song, Lulu Liu, Xuting Wu, Jinxin Wang, Li Xue
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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. 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摘要

背景:内脏脂肪组织源性丝氨酸蛋白酶抑制剂(vaspin)是一种分泌性脂肪因子,可预防胰岛素抵抗。最近的研究表明,冠状动脉疾病患者血清血管素水平降低,血管素对心肌缺血再灌注损伤和动脉粥样硬化具有保护作用。然而,vaspin是否对病理性心肌肥厚具有特异性作用尚不清楚。方法采用皮下注射异丙肾上腺素(ISO)建立C57BL/6和vaspin-ko小鼠心肌肥厚模型进行体内研究。小鼠腹腔注射雷帕霉素,以作进一步研究。用ISO诱导H9c2细胞和新生大鼠心室肌细胞(nrvm)肥大。使用人血管蛋白融合蛋白、蛋白酶体抑制剂MG132和二磷酸氯喹进行进一步的机制研究。在这里,我们提供了第一个证据,表明vaspin敲低导致ISO处理小鼠心肌肥大、纤维化和心肌细胞衰老明显加剧。相反,外源性重组人vaspin在体外保护nrvm免受iso诱导的肥大和衰老。此外,vaspin显著增强了iso诱导的自噬减少。雷帕霉素和二磷酸氯喹分别在体内和体外调节自噬,并参与血管素介导的心脏保护。此外,PI3K-AKT-mTOR通路在血管素介导的心脏组织和nrvm自噬中起关键作用。我们的数据显示,vaspin通过将p85和p110与nedd4l介导的泛素化降解联系起来,下调了PI3K的p85和p110亚基。结论我们的研究结果首次表明,vaspin是通过调节自噬依赖性心肌衰老来减轻病理性心肌肥厚的关键调节剂,为病理性心肌肥厚提供了潜在的预防和治疗靶点。
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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.
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