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PCSK9 increases vulnerability of carotid plaque by promoting mitochondrial dysfunction and apoptosis of vascular smooth muscle cells

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机构： [1]Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China. [2]China International Neuroscience Institute (China-INI), Beijing, China. [3]School of Public Health and Center for Statistical Science, Peking University, Beijing, China. [4]Neuroendovascular Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. [5]Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China. [6]School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China. [7]Department of Interventional Neuroradiology, Xuanwu Hospital, Capital Medical University, Beijing, China. [8]Daepartment of Neurosurgery and Neurology, Jinan Hospital of Xuanwu Hospital, Shandong First Medical University, Jinan, China.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a novel lipid-lowing target. Recent clinical studies suggested the value of inhibiting PCSK9 in decreasing the vulnerability of coronary plaques. However, the evidence of PCSK9-regulated evolution of unstable carotid plaques is unclear, which has limited the use of PCSK9 inhibitor in carotid plaques. This study aimed to determine the effect and molecular mechanisms of PCSK9 on vulnerability of carotid plaques, to provide potential therapeutic targets for stabilizing carotid plaques.The expression of PCSK9 in stable and unstable carotid plaques were examined in tissue and plasma. Human aortic vascular smooth muscle cells (VSMCs) and carotid VSMCs were employed to transfect lentivirus for overexpression and knockdown of PCSK9, respectively. Morphological and functional changes of mitochondria were observed by live-cell imaging. Cell apoptosis was evaluated by propidium iodide staining. RNA-sequencing and biological examinations were performed to explore and validate the underlying mechanisms. Truncated plasmids were employed to identify the functional domain of PCSK9 in regulation of VSMCs' mitochondrial morphology, function and apoptosis.Clinically, PCSK9 was closely related with vulnerability of human carotid plaques. Increased expression of PCSK9 in human VSMCs was accompanied by higher level of apoptosis. At subcellular level of VSMCs, the morphology of mitochondria was shifted toward the fission state, followed by mitochondrial dysfunction. Inhibition of p38 MAPK activation partially rescued the above morphological and behavioral changes caused by PCSK9. Furthermore, inhibiting of dynamin-related protein 1 (DRP1) attenuated PCSK9-related mitochondrial dysfunction and cell apoptosis. The 1-149aa domain of PCSK9 protein was essential to achieve functional regulation to VSMCs.Our findings demonstrated that PCSK9 induced morphology-related mitochondrial dysfunction and apoptosis of VSMCs, which may be related to increased vulnerability of carotid plaque.© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

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出版当年[2023]版：

大类 | 1 区医学

小类 | 2 区神经科学 2 区药学

最新[2023]版：

大类 | 1 区医学

小类 | 2 区神经科学 2 区药学

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出版当年[2022]版：

Q1 NEUROSCIENCES Q1 PHARMACOLOGY & PHARMACY

最新[2023]版：

Q1 PHARMACOLOGY & PHARMACY Q1 NEUROSCIENCES

影响因子： 4.8 最新[2023版] 5.9 最新五年平均 5.5 出版当年[2022版] 6.2 出版当年五年平均 7.035 出版前一年[2021版] 4.8 出版后一年[2023版]

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第一作者机构： [1]Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China. [2]China International Neuroscience Institute (China-INI), Beijing, China.

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通讯作者：

通讯机构： [1]Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China. [2]China International Neuroscience Institute (China-INI), Beijing, China. [5]Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China. [6]School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China. [7]Department of Interventional Neuroradiology, Xuanwu Hospital, Capital Medical University, Beijing, China. [8]Daepartment of Neurosurgery and Neurology, Jinan Hospital of Xuanwu Hospital, Shandong First Medical University, Jinan, China. [*1]Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China. [*2]Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.

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