Chen Zhe, Zhou Qionglin, Chen Jun, Yang Yiyuan, Chen Wei, Mao Hui, Ouyang Xueqian, Zhang Kai, Tang Mingzhu, Yan Jialong, Wang Linzhi, Chen Linxi, Li Lanfang
Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of tumor microenvironment responsive drug research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, College of Basic Medical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of tumor microenvironment responsive drug research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, College of Basic Medical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
Vascul Pharmacol. 2022 Jun;144:106979. doi: 10.1016/j.vph.2022.106979. Epub 2022 Mar 17.
Apelin is an endogenous ligand of the G protein-coupled receptor APJ. Both apelin and APJ receptors, which are expressed in vascular smooth muscle cells (VSMCs), play important roles in the cardiovascular system. Our previous studies researches indicated that mitophagy mediated apelin-13-induced VSMCs proliferation. However, little is known about how apelin-13 regulates mitophagy to participate in VSMC proliferation. The results of the present study demonstrated that mitochondrial calcium uniporter (MCU) uptake-dependent mitochondrial calcium-induced mitophagy is involved in apelin-13-induced VSMCs proliferation. Apelin-13 promoted the expression of MCU which increases mitochondrial calcium uptake. Apelin-13-induced MCU-dependent mitochondrial calcium uptake further increased mitochondrial ROS (mtROS) concentrations and promoted mitophagy, which can be evidenced through the upregulation of the Dynamin-related protein 1(Drp1), PTEN-induced kinase 1 (PINK1), and Parkin. The clearance of mtROS by Mito-TEMPO significantly reversed apelin-13-induced mitophagy. Moreover, both the Drp1 inhibitor mdivi-1 and siRNA-Drp1 inhibited apelin-13-induced mitophagy. Furthermore, the APJ receptor antagonist F13A, MCU inhibitor Ru360, mitochondria-targeted antioxidant Mito-TEMPO, Drp1 inhibitor Mdivi-1, siRNA-Drp1, siRNA-PINK1, and siRNA-Parkin inhibited the proliferation of VSMCs induced by apelin-13. In ApoE mice, intraperitoneal administration of apelin-13 induced the expression of MCU, Drp1, PINK1, Parkin, and α-SMA and increased atherosclerotic plaque lesions. However, F13A and Ru360 decreased the expression of MCU, Drp1, PINK1, Parkin, and α-SMA and reduced atherosclerotic plaque lesions in ApoE mice injected with apelin-13. Collectively, our results demonstrate that MCU-dependent mitochondrial calcium uptake-induced mitophagy is involved in apelin-13-stimulated VSMCs proliferation.
Apelin是G蛋白偶联受体APJ的内源性配体。Apelin和APJ受体均在血管平滑肌细胞（VSMC）中表达，它们在心血管系统中发挥重要作用。我们之前的研究表明，线粒体自噬介导了apelin-13诱导的VSMC增殖。然而，关于apelin-13如何调节线粒体自噬以参与VSMC增殖，人们了解甚少。本研究结果表明，线粒体钙单向转运体（MCU）摄取依赖性线粒体钙诱导的线粒体自噬参与了apelin-13诱导的VSMC增殖。Apelin-13促进了MCU的表达，从而增加了线粒体钙摄取。Apelin-13诱导的MCU依赖性线粒体钙摄取进一步增加了线粒体活性氧（mtROS）浓度并促进了线粒体自噬，这可以通过动力相关蛋白1（Drp1）、PTEN诱导激酶1（PINK1）和Parkin的上调得到证明。Mito-TEMPO清除mtROS显著逆转了apelin-13诱导的线粒体自噬。此外，Drp1抑制剂mdivi-1和siRNA-Drp1均抑制了apelin-13诱导的线粒体自噬。此外，APJ受体拮抗剂F13A、MCU抑制剂Ru360、线粒体靶向抗氧化剂Mito-TEMPO、Drp1抑制剂Mdivi-1、siRNA-Drp1、siRNA-PINK1和siRNA-Parkin均抑制了apelin-13诱导的VSMC增殖。在载脂蛋白E（ApoE）小鼠中，腹腔注射apelin-13诱导了MCU、Drp1、PINK1、Parkin和α-平滑肌肌动蛋白（α-SMA）的表达，并增加了动脉粥样硬化斑块病变。然而，F13A和Ru360降低了注射apelin-13的ApoE小鼠中MCU、Drp1、PINK1、Parkin和α-SMA的表达，并减少了动脉粥样硬化斑块病变。总的来说，我们的结果表明，MCU依赖性线粒体钙摄取诱导的线粒体自噬参与了apelin-13刺激的VSMC增殖。
