Mitochondrial Damage-Induced Innate Immune Activation in Vascular Smooth Muscle Cells Promotes Chronic Kidney Disease-Associated Plaque Vulnerability.
Mitochondrial Damage-Induced Innate Immune Activation in Vascular Smooth Muscle Cells Promotes Chronic Kidney Disease-Associated Plaque Vulnerability.
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线粒体损伤——血管平滑肌细胞中诱导的先天免疫激活促进慢性肾脏病——相关的斑块脆弱性
DOI：
10.1002/advs.202002738
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Zhao J
中科院分区：
文献类型：
--
作者：
Bi X;Du C;Wang X;Wang XY;Han W;Wang Y;Qiao Y;Zhu Y;Ran L;Liu Y;Xiong J;Huang Y;Liu M;Liu C;Zeng C;Wang J;Yang K;Zhao J
慢性肾脏病（CKD）与动脉粥样硬化进展加速和心血管事件的高发生率相关，提示CKD中的动脉粥样硬化斑块可能是脆弱的。然而，其原因和机制仍不清楚。在此，研究表明，载脂蛋白E-缺陷（ApoE-/-）CKD小鼠（CKD/ApoE-/-小鼠）是研究斑块脆弱性发病机制的有用模型，血管平滑肌细胞（VSMC）的过早衰老和表型转换有助于CKD相关斑块脆弱性。随后，全面研究了CKD患者和CKD/ApoE −/−小鼠的VSMC表型。使用多组学分析和靶向和VSMC特异性基因敲除小鼠，VSMC被鉴定为I型干扰素（IFN-I）应答性和IFN-I生产性细胞。从机制上讲，由CKD诱导的氧化应激引起的线粒体损伤启动了干扰素基因的环GMP-AMP合酶刺激因子（cGAS-STING）途径，以触发VSMC中的IFN-I反应。增强的IFN-I反应然后以自分泌/旁分泌方式诱导VSMC过早衰老和表型转换，导致纤维帽VSMC的损失和纤维帽变薄。相反，阻断IFN-I反应可显著减弱CKD相关斑块的脆弱性。这些研究结果表明，VSMC中通过线粒体损伤的免疫感应产生的IFN-I反应对于CKD相关斑块脆弱性的发病机制至关重要。减轻IFN-I反应可能有望用于治疗CKD相关心血管疾病。
Chronic kidney disease (CKD) is associated with accelerated atherosclerosis progression and high incidence of cardiovascular events, hinting that atherosclerotic plaques in CKD may be vulnerable. However, its cause and mechanism remain obscure. Here, it is shown that apolipoprotein E‐deficient (ApoE−/−) mouse with CKD (CKD/ApoE−/− mouse) is a useful model for investigating the pathogenesis of plaque vulnerability, and premature senescence and phenotypic switching of vascular smooth muscle cells (VSMCs) contributes to CKD‐associated plaque vulnerability. Subsequently, VSMC phenotypes in patients with CKD and CKD/ApoE−/− mice are comprehensively investigated. Using multi‐omics analysis and targeted and VSMC‐specific gene knockout mice, VSMCs are identified as both type‐I‐interferon (IFN‐I)‐responsive and IFN‐I‐productive cells. Mechanistically, mitochondrial damage resulting from CKD‐induced oxidative stress primes the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway to trigger IFN‐I response in VSMCs. Enhanced IFN‐I response then induces VSMC premature senescence and phenotypic switching in an autocrine/paracrine manner, resulting in the loss of fibrous cap VSMCs and fibrous cap thinning. Conversely, blocking IFN‐I response remarkably attenuates CKD‐associated plaque vulnerability. These findings reveal that IFN‐I response in VSMCs through immune sensing of mitochondrial damage is essential for the pathogenesis of CKD‐associated plaque vulnerability. Mitigating IFN‐I response may hold promise for the treatment of CKD‐associated cardiovascular diseases.
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DOI：
10.1056/nejmoa1312625
发表时间：
2014-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Liu Y;Jesus AA;Marrero B;Yang D;Ramsey SE;Sanchez GAM;Tenbrock K;Wittkowski H;Jones OY;Kuehn HS;Lee CR;DiMattia MA;Cowen EW;Gonzalez B;Palmer I;DiGiovanna JJ;Biancotto A;Kim H;Tsai WL;Trier AM;Huang Y;Stone DL;Hill S;Kim HJ;St Hilaire C;Gurprasad S;Plass N;Chapelle D;Horkayne-Szakaly I;Foell D;Barysenka A;Candotti F;Holland SM;Hughes JD;Mehmet H;Issekutz AC;Raffeld M;McElwee J;Fontana JR;Minniti CP;Moir S;Kastner DL;Gadina M;Steven AC;Wingfield PT;Brooks SR;Rosenzweig SD;Fleisher TA;Deng Z;Boehm M;Paller AS;Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R
影响因子：
168.9
作者：
Jha, Vivekanand;Garcia-Garcia, Guillermo;Yang, Chih-Wei
通讯作者：
Yang, Chih-Wei
DOI：
10.1084/jem.20180139
发表时间：
2018-05-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li T;Chen ZJ
通讯作者：
Chen ZJ
影响因子：
10.8
作者：
Bauriedel, G;Hutter, R;Lüderitz, B
通讯作者：
Lüderitz, B
DOI：
10.1016/s0022-5320(61)80002-6
发表时间：
1961-01-01
期刊：
JOURNAL OF ULTRASTRUCTURE RESEARCH
影响因子：
--
作者：
KARRER, HE
通讯作者：
KARRER, HE