SVEP1 is a human coronary artery disease locus that promotes atherosclerosis.
SVEP1 is a human coronary artery disease locus that promotes atherosclerosis.
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SVEP1是促进动脉粥样硬化的人类冠状动脉疾病位点。
DOI：
10.1126/scitranslmed.abe0357
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发表时间：
2021-03-24
影响因子：
17.1
通讯作者：
Stitziel NO
中科院分区：
文献类型：
--
作者：
Jung IH;Elenbaas JS;Alisio A;Santana K;Young EP;Kang CJ;Kachroo P;Lavine KJ;Razani B;Mecham RP;Stitziel NO
寿司，血管性血友病因子A型，EGF和含五聚体结构域蛋白1（SVEP 1）的低频变体，一种细胞外基质蛋白，与人类冠状动脉疾病的风险相关，不依赖于血脂。尽管存在强有力的统计学相关性，但SVEP 1是否以及如何促进动脉粥样硬化仍不清楚。在这里，使用孟德尔随机化和互补的小鼠模型，我们提供的证据表明，SVEP 1促进人类和小鼠的动脉粥样硬化，并在动脉粥样硬化斑块内的血管平滑肌细胞（VSMC）表达。VSMC还与SVEP 1相互作用，导致增殖和关键分化途径的失调，包括整合素和Notch信号传导。成纤维细胞生长因子受体的转录在与SVEP 1相互作用的VSMC中增加，并且通过冠状动脉疾病相关的SVEP 1变体p.D2702G进一步增加。这些作用最终会导致炎症并促进动脉粥样硬化。总之，我们的研究结果表明，VSMC衍生的SVEP 1是一个促动脉粥样硬化因子，并支持这一概念，即药物抑制SVEP 1应防止人类动脉粥样硬化。降低SVEP 1可以保护动脉粥样硬化，并可能成为治疗和预防冠状动脉疾病的治疗靶点。
A low-frequency variant of sushi, von Willebrand factor type A, EGF and pentraxin domain containing protein 1 (SVEP1), an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, if and how SVEP1 might contribute to atherosclerosis remained unclear. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice and is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1, and is further increased by the coronary disease-associated SVEP1 variant p.D2702G. These effects ultimately drive inflammation and promote atherosclerosis. Taken together, our results suggest that VSMC-derived SVEP1 is a pro-atherogenic factor, and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans. Reducing SVEP1 confers protection from atherosclerosis and may be a therapeutic target for the treatment and prevention of coronary artery disease.
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影响因子：
5.3
作者：
Andrews, Melissa R.;Czvitkovich, Stefan;Fawcett, James W.
通讯作者：
Fawcett, James W.
影响因子：
5.3
作者：
Huang, XZ;Wu, JF;Sheppard, D
通讯作者：
Sheppard, D
DOI：
10.1083/jcb.201008013
发表时间：
2011-10-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Danussi C;Petrucco A;Wassermann B;Pivetta E;Modica TM;Del Bel Belluz L;Colombatti A;Spessotto P
通讯作者：
Spessotto P
影响因子：
9.3
作者：
Cangemi, Claudia;Skov, Vibe;Rasmussen, Lars Melholt
通讯作者：
Rasmussen, Lars Melholt
影响因子：
82.9
作者：
Cherepanova OA;Gomez D;Shankman LS;Swiatlowska P;Williams J;Sarmento OF;Alencar GF;Hess DL;Bevard MH;Greene ES;Murgai M;Turner SD;Geng YJ;Bekiranov S;Connelly JJ;Tomilin A;Owens GK
通讯作者：
Owens GK