Functional investigation of the coronary artery disease gene SVEP1
- PDF / 2,630,739 Bytes
- 15 Pages / 595.276 x 790.866 pts Page_size
- 11 Downloads / 211 Views
ORIGINAL CONTRIBUTION
Functional investigation of the coronary artery disease gene SVEP1 Michael J. Winkler1,2 · Philipp Müller1,2 · Amin M. Sharifi1,2 · Jana Wobst1,2 · Hanna Winter2,3 · Michal Mokry4 · Lijiang Ma5 · Sander W. van der Laan4 · Shichao Pang1 · Benedikt Miritsch1,2 · Julia Hinterdobler1,2 · Julia Werner1,2 · Barbara Stiller1 · Ulrich Güldener1 · Tom R. Webb6 · Folkert W. Asselbergs4,7 · Johan L. M. Björkegren5,8,9 · Lars Maegdefessel2,3 · Heribert Schunkert1,2 · Hendrik B. Sager1,2 · Thorsten Kessler1,2 Received: 15 August 2020 / Accepted: 26 October 2020 © The Author(s) 2020
Abstract 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, L y6Chigh mono−/− cyte, 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. Keywords SVEP1 · Atherosclerosis · Coronary artery disease · Genetics
Introduction Coronary artery disease (CAD) and myocardial infarction (MI) are the leading causes of death in industrialized countries [4]. Genome-wide association studies have identified more than 160 variants, mainly located in the non-coding genome, that are associated with CAD/MI [13]. In an Michael J. Winkler and Philipp Müller contributed equally. Hendrik B. Sager and Thorsten Kessler contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00395-020-00828-6) contains supplementary material, which is available to authorized users. * Hendrik B. Sager [email protected] * Thorsten Kessler [email protected] Extended author information available on the last page of the article
exome-wide association study, a coding missense variant in SVEP1 (rs111245230, p.D2702G) is genome-wide significantly associated with CAD/MI (Odds Ratio 1.14 per ris
Data Loading...
