@article{4b3364714f4a4e28ba38d463f751cb07,
title = "Functional investigation of the coronary artery disease gene SVEP1",
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, 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.",
keywords = "Atherosclerosis, Coronary artery disease, Genetics, SVEP1",
author = "Winkler, {Michael J} and Philipp M{\"u}ller and Sharifi, {Amin M} and Jana Wobst and Hanna Winter and Michal Mokry and Lijiang Ma and {van der Laan}, {Sander W} and Shichao Pang and Benedikt Miritsch and Julia Hinterdobler and Julia Werner and Barbara Stiller and Ulrich G{\"u}ldener and Webb, {Tom R} and Asselbergs, {Folkert W} and Bj{\"o}rkegren, {Johan L M} and Lars Maegdefessel and Heribert Schunkert and Sager, {Hendrik B} and Thorsten Kessler",
note = "Funding Information: Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Corona Foundation as part of the Junior Research Group Translational Cardiovascular Genomics (S199/10070/2017, to T.K.) and the German Research Foundation (DFG) as part of the collaborative research centers SFB 1123 (B02, to T.K. and H.S.); TRR 267 (B06, to H.S.); and STRESS_638675 (to H.B.S.). Additional grants were received from the European Research Council under the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement No 759272, to H.B.S.), the Else-Kr{\"o}ner-Fresenius-Stiftung (2020_EKSE.07, to H.B.S.), the German Heart Foundation (Deutsche Herzstiftung; F/28/17, to H.B.S.), and the German Federal Ministry of Education and Research within the framework of ERA-NET on Cardiovascular Disease (ERA-CVD: grant JTC2017_21-040, to H.S., J.B., and F.W.A.) and within the scheme of target validation (BlockCAD: 6GW0198K, to H.S.). Additional support was received from the British Heart Foundation/DZHK collaborative project “Genetic discovery-based targeting of the vascular interface in atherosclerosis”. F.W.A. is supported by UCL Hospitals NIHR Biomedical Research Centre. J.L.M.B. acknowledges research support from the National Institutes of Health (R01HL125863), the American Heart Association (A14SFRN20840000), the Swedish Research Council (2018-02529) and Heart Lung Foundation (20170265), the Foundation Leducq (PlaqueOmics, 18CVD02) and by Astra-Zeneca through Integrated Cardio Metabolic Centre, Karolinska Institutet, Sweden. Acknowledgements Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = nov,
day = "13",
doi = "10.1007/s00395-020-00828-6",
language = "English",
volume = "115",
pages = "1--15",
journal = "Basic Research in Cardiology",
issn = "0300-8428",
publisher = "D. Steinkopff-Verlag",
number = "6",
}