Functional investigation of the coronary artery disease gene SVEP1

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 smoo...

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Bibliographic Details
Published in:	Basic research in cardiology Vol. 115; no. 6; p. 67
Main Authors:	Winkler, Michael J., Müller, Philipp, Sharifi, Amin M., Wobst, Jana, Winter, Hanna, Mokry, Michal, Ma, Lijiang, van der Laan, Sander W., Pang, Shichao, Miritsch, Benedikt, Hinterdobler, Julia, Werner, Julia, Stiller, Barbara, Güldener, Ulrich, Webb, Tom R., Asselbergs, Folkert W., Björkegren, Johan L. M., Maegdefessel, Lars, Schunkert, Heribert, Sager, Hendrik B., Kessler, Thorsten
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 2020 Springer Nature B.V
Subjects:	Animals Antigens, Ly - metabolism Apolipoprotein E Arteriosclerosis Atherosclerosis Blood Calcium-Binding Proteins - deficiency Calcium-Binding Proteins - genetics Calcium-Binding Proteins - metabolism Cardiology Cardiovascular disease Cell Adhesion Molecules - deficiency Cell Adhesion Molecules - genetics Cell Adhesion Molecules - metabolism Cells, Cultured Chemokine CXCL1 - genetics Chemokine CXCL1 - metabolism Chemokines Chemotaxis, Leukocyte Coronary artery Coronary artery disease Coronary Artery Disease - genetics Coronary Artery Disease - metabolism Coronary Artery Disease - pathology Coronary vessels Coronary Vessels - metabolism Coronary Vessels - pathology Disease Models, Animal Endothelial cells Endothelial Cells - metabolism Endothelial Cells - pathology Genetic Association Studies Genetic Predisposition to Disease Genomes Haploinsufficiency Heart diseases Humans Incubation Inflammation Leukocyte migration Leukocytes Macrophages Macrophages - metabolism Medicin och hälsovetenskap Medicine Medicine & Public Health Mice, Inbred C57BL Mice, Knockout, ApoE Monocytes Muscles Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Neutrophil Infiltration Neutrophils - pathology Original Contribution Pentraxins Plaque, Atherosclerotic Plaques Polymorphism, Single Nucleotide Proteins - genetics Proteins - metabolism Recruitment Smooth muscle Von Willebrand factor Genetics SVEP1 Coronary artery disease Atherosclerosis
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Summary:	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, Ly6C high 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0300-8428 1435-1803 1435-1803
DOI:	10.1007/s00395-020-00828-6