Functional investigation of the coronary artery disease gene SVEP1.
Functional investigation of the coronary artery disease gene SVEP1.
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DOI：
10.1007/s00395-020-00828-6
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发表时间：
2020-11-13
影响因子：
9.5
通讯作者：
Kessler T
中科院分区：
文献类型：
--
作者：
Winkler MJ;Müller P;Sharifi AM;Wobst J;Winter H;Mokry M;Ma L;van der Laan SW;Pang S;Miritsch B;Hinterdobler J;Werner J;Stiller B;Güldener U;Webb TR;Asselbergs FW;Björkegren JLM;Maegdefessel L;Schunkert H;Sager HB;Kessler T
寿司、von Willebrand因子A型、EGF和五角蛋白结构域包含蛋白1(SVEP1)的错义变体在全基因组范围内与冠状动脉疾病显著相关。SVEP1如何影响动脉粥样硬化的机制尚不清楚。我们发现血管内皮细胞和血管平滑肌细胞是斑块中SVEP1的主要细胞来源。与野生型Svep1小鼠(ApoE−/−Svep1+/+)相比，易发生动脉粥样硬化的Svep1单倍体缺陷小鼠(ApoE−/−Svep1+/−)的斑块较大，且ApoE−/−Svep1+/−/−小鼠的斑块中性粒细胞、单核细胞和巨噬细胞数量增加。我们评估了ApoE−/−Svep1+/−小鼠的白细胞如何在斑块内积累更多，并发现白细胞从血液中募集到斑块中的能力增强。在体外，我们研究了SVEP1缺乏如何促进白细胞募集，并发现与野生型SVEP1相比，错义培养的EC中白细胞趋化因子(C-X-C基序)配体1(CXCL1)的表达增加。增加野生型SVEP1水平可抑制内皮细胞CXCL1的释放。同样，ApoE−/−Svep1+/−小鼠血浆CXCL1水平升高。我们的研究揭示了SVEP1的动脉粥样硬化保护作用。缺乏野生型Svep1增加了内皮细胞CXCL1的表达，导致促炎症白细胞从血液到斑块的募集增加。因此，血管炎症加剧导致Svep1缺乏症斑块进展加快。本文的在线版本(10.1007/s00395-020-00828-6)包含向授权用户提供的补充材料。
A missense variant of the sushi, von Willebrand factor type A, EGF and pentraxin domain containing protein 1 (SVEP1) is genome-wide significantly associated with coronary artery disease. The mechanisms how SVEP1 impacts atherosclerosis are not known. We found endothelial cells (EC) and vascular smooth muscle cells to represent the major cellular source of SVEP1 in plaques. Plaques were larger in atherosclerosis-prone Svep1 haploinsufficient (ApoE−/−Svep1+/−) compared to Svep1 wild-type mice (ApoE−/−Svep1+/+) and ApoE−/−Svep1+/− mice displayed elevated plaque neutrophil, Ly6Chigh monocyte, and macrophage numbers. We assessed how leukocytes accumulated more inside plaques in ApoE−/−Svep1+/− mice and found enhanced leukocyte recruitment from blood into plaques. In vitro, we examined how SVEP1 deficiency promotes leukocyte recruitment and found elevated expression of the leukocyte attractant chemokine (C-X-C motif) ligand 1 (CXCL1) in EC after incubation with missense compared to wild-type SVEP1. Increasing wild-type SVEP1 levels silenced endothelial CXCL1 release. In line, plasma Cxcl1 levels were elevated in ApoE−/−Svep1+/− mice. Our studies reveal an atheroprotective role of SVEP1. Deficiency of wild-type Svep1 increased endothelial CXCL1 expression leading to enhanced recruitment of proinflammatory leukocytes from blood to plaque. Consequently, elevated vascular inflammation resulted in enhanced plaque progression in Svep1 deficiency. The online version of this article (10.1007/s00395-020-00828-6) contains supplementary material, which is available to authorized users.
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影响因子：
11.8
作者：
Bazigou, Eleni;Xie, Sherry;Chen, Chun;Weston, Anne;Miura, Naoyuki;Sorokin, Lydia;Adams, Ralf;Muro, Andres F.;Sheppard, Dean;Makinen, Taija
通讯作者：
Makinen, Taija
影响因子：
20.1
作者：
Karpanen T;Padberg Y;van de Pavert SA;Dierkes C;Morooka N;Peterson-Maduro J;van de Hoek G;Adrian M;Mochizuki N;Sekiguchi K;Kiefer F;Schulte D;Schulte-Merker S
通讯作者：
Schulte-Merker S
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
DOI：
10.1126/science.aad6970
发表时间：
2016-08-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franzén O;Ermel R;Cohain A;Akers NK;Di Narzo A;Talukdar HA;Foroughi-Asl H;Giambartolomei C;Fullard JF;Sukhavasi K;Köks S;Gan LM;Giannarelli C;Kovacic JC;Betsholtz C;Losic B;Michoel T;Hao K;Roussos P;Skogsberg J;Ruusalepp A;Schadt EE;Björkegren JL
通讯作者：
Björkegren JL
影响因子：
6.1
作者：
Okolo, SO;Gentry, CC;Maclean, AB
通讯作者：
Maclean, AB