Institute of Pharmacy and Pharmacology, Province Cooperative Innovation Center for Molecular Target New Drug Study, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang, China.
Department of Neurosurgery, First Affiliated Hospital, University of South China, Hengyang, China.
J Cell Physiol. 2019 Jun;234(6):8668-8682. doi: 10.1002/jcp.27527. Epub 2018 Nov 19.
Aberrant proliferation of vascular smooth muscle cells (VSMC) is a critical contributor to the pathogenesis of atherosclerosis (AS). Our previous studies have demonstrated that apelin-13/APJ confers a proliferative response in VSMC, however, its underlying mechanism remains elusive. In this study, we aimed to investigate the role of mitophagy in apelin-13-induced VSMC proliferation and atherosclerotic lesions in apolipoprotein E knockout (ApoE-/-) mice. Apelin-13 enhances human aortic VSMC proliferation and proliferative regulator proliferating cell nuclear antigen expression in dose and time-dependent manner, while is abolished by APJ antagonist F13A. We observe the engulfment of damage mitochondria by autophagosomes (mitophagy) of human aortic VSMC in apelin-13 stimulation. Mechanistically, apelin-13 increases p-AMPKα and promotes mitophagic activity such as the LC3I to LC3II ratio, the increase of Beclin-1 level and the decrease of p62 level. Importantly, the expressions of PINK1, Parkin, VDAC1, and Tom20 are induced by apelin-13. Conversely, blockade of APJ by F13A abolishes these stimulatory effects. Human aortic VSMC transfected with AMPKα, PINK1, or Parkin and subjected to apelin-13 impairs mitophagy and prevents proliferation. Additional, apelin-13 not only increases the expression of Drp1 but also reduces the expressions of Mfn1, Mfn2, and OPA1. Remarkably, the mitochondrial division inhibitor-1(Mdivi-1), the pharmacological inhibition of Drp1, attenuates human aortic VSMC proliferation. Treatment of ApoE-/- mice with apelin-13 accelerates atherosclerotic lesions, increases p-AMPKα and mitophagy in aortic wall in vivo. Finally, PINK1-/- mutant mice with apelin-13 attenuates atherosclerotic lesions along with defective in mitophagy. PINK1/Parkin-mediated mitophagy promotes apelin-13-evoked human aortic VSMC proliferation by activating p-AMPKα and exacerbates the progression of atherosclerotic lesions.
血管平滑肌细胞（VSMC）的异常增殖是动脉粥样硬化（AS）发病机制的关键因素。我们之前的研究表明，apelin-13/APJ 赋予 VSMC 增殖反应，但其潜在机制尚不清楚。在这项研究中，我们旨在研究细胞自噬在 apelin-13 诱导的 VSMC 增殖和载脂蛋白 E 敲除（ApoE-/-）小鼠动脉粥样硬化病变中的作用。apelin-13 以剂量和时间依赖的方式增强人主动脉 VSMC 的增殖和增殖调节因子增殖细胞核抗原的表达，而 APJ 拮抗剂 F13A 则使其丧失作用。我们观察到 apelin-13 刺激下人主动脉 VSMC 中的损伤线粒体被自噬体（自噬）吞噬。在机制上，apelin-13 增加 p-AMPKα，并促进自噬活性，如 LC3I 向 LC3II 的转化、Beclin-1 水平的增加和 p62 水平的降低。重要的是，apelin-13 诱导 PINK1、Parkin、VDAC1 和 Tom20 的表达。相反，APJ 被 F13A 阻断则会消除这些刺激作用。转染 AMPKα、PINK1 或 Parkin 并接受 apelin-13 处理的人主动脉 VSMC 会损害自噬并阻止增殖。此外，apelin-13 不仅增加 Drp1 的表达，还降低 Mfn1、Mfn2 和 OPA1 的表达。值得注意的是，线粒体分裂抑制剂-1（Mdivi-1），Drp1 的药理学抑制，可减轻人主动脉 VSMC 的增殖。用 apelin-13 治疗 ApoE-/-小鼠可加速动脉粥样硬化病变，并在体内增加主动脉壁中的 p-AMPKα 和自噬。最后，用 apelin-13 处理的 PINK1-/- 突变小鼠减轻了动脉粥样硬化病变，同时自噬受损。PINK1/Parkin 介导的自噬通过激活 p-AMPKα 促进 apelin-13 引发的人主动脉 VSMC 增殖，并加剧动脉粥样硬化病变的进展。
