Yu Wancheng, Mei Xu, Zhang Qian, Zhang Haizhou, Zhang Tao, Zou Chengwei
a Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University , Jinan , China.
b Department of Geriatrics, Shandong University Qilu Hospital , Jinan , China.
J Recept Signal Transduct Res. 2019 Apr;39(2):175-186. doi: 10.1080/10799893.2019.1641822. Epub 2019 Jul 29.
Yes-associated protein (Yap) has been linked to several cardiovascular disorders, but the role of this protein in septic cardiomyocytes is not fully understood. The aim of our study was to explore the influence of Yap in septic cardiomyopathy and . In the current study, Yap transgenic mice and Yap adenovirus-mediated gain-of-function assays were used in an LPS-established septic cardiomyopathy model. Mitochondrial function and mitochondrial fission were determined through western blotting, immunofluorescence analysis and ELISA. Our results demonstrated that Yap expression was downregulated by LPS, whereas Yap overexpression sustained cardiac function and attenuated cardiomyocyte death. The functional exploration revealed that LPS treatment induced cardiomyocyte mitochondrial stress, as manifested by mitochondrial superoxide overproduction, cardiomyocyte ATP deprivation, and caspase-9 apoptosis activation. Furthermore, we demonstrated that LPS-mediated mitochondrial damage was controlled by mitochondrial fission. However, Yap overexpression reduced mitochondrial fission and therefore improved mitochondrial function. A molecular investigation revealed that Yap overexpression inhibited mitochondrial fission by reversing ERK activity, and the inhibition of the ERK pathway promoted DRP1 upregulation and thereby mediated mitochondrial fission activation in the presence of Yap overexpression. Overall, our results suggest that the cause of septic cardiomyopathy appears to be connected with Yap downregulation. The overexpression of Yap can attenuate myocardial inflammation injury through the reduction of DRP1-related mitochondrial fission in an ERK pathway activation-dependent manner.
Yes相关蛋白（Yap）已被证实与多种心血管疾病有关，但该蛋白在脓毒症心肌细胞中的作用尚未完全明确。本研究旨在探讨Yap在脓毒症心肌病中的影响。在本研究中，Yap转基因小鼠和Yap腺病毒介导的功能获得性实验被应用于脂多糖（LPS）诱导建立的脓毒症心肌病模型。通过蛋白质免疫印迹法、免疫荧光分析和酶联免疫吸附测定法来检测线粒体功能和线粒体分裂情况。我们的研究结果表明，LPS可下调Yap的表达，而Yap的过表达则可维持心脏功能并减轻心肌细胞死亡。功能探究显示，LPS处理可诱导心肌细胞线粒体应激，表现为线粒体超氧化物过量产生、心肌细胞ATP耗竭以及半胱天冬酶-9凋亡激活。此外，我们还证实LPS介导的线粒体损伤受线粒体分裂调控。然而，Yap的过表达可减少线粒体分裂，从而改善线粒体功能。分子研究表明，Yap过表达通过逆转细胞外信号调节激酶（ERK）活性来抑制线粒体分裂，并且在Yap过表达的情况下，ERK通路的抑制会促进动力相关蛋白1（DRP1）上调，进而介导线粒体分裂激活。总体而言，我们的研究结果表明脓毒症心肌病的病因似乎与Yap下调有关。Yap的过表达可通过依赖ERK通路激活减少DRP1相关的线粒体分裂，从而减轻心肌炎症损伤。
