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Functional investigation of the coronary artery disease gene SVEP1.
- Source :
-
Basic research in cardiology [Basic Res Cardiol] 2020 Nov 13; Vol. 115 (6), pp. 67. Date of Electronic Publication: 2020 Nov 13. - Publication Year :
- 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 <superscript>-/-</superscript> Svep1 <superscript>+/-</superscript> ) compared to Svep1 wild-type mice (ApoE <superscript>-/-</superscript> Svep1 <superscript>+/+</superscript> ) and ApoE <superscript>-/-</superscript> Svep1 <superscript>+/-</superscript> mice displayed elevated plaque neutrophil, Ly6C <superscript>high</superscript> monocyte, and macrophage numbers. We assessed how leukocytes accumulated more inside plaques in ApoE <superscript>-/-</superscript> Svep1 <superscript>+/-</superscript> 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 <superscript>-/-</superscript> Svep1 <superscript>+/-</superscript> 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.
- Subjects :
- Animals
Antigens, Ly metabolism
Calcium-Binding Proteins deficiency
Calcium-Binding Proteins genetics
Cell Adhesion Molecules deficiency
Cell Adhesion Molecules genetics
Cells, Cultured
Chemokine CXCL1 genetics
Chemokine CXCL1 metabolism
Chemotaxis, Leukocyte
Coronary Artery Disease genetics
Coronary Artery Disease pathology
Coronary Vessels pathology
Disease Models, Animal
Endothelial Cells metabolism
Endothelial Cells pathology
Genetic Association Studies
Genetic Predisposition to Disease
Haploinsufficiency
Humans
Macrophages metabolism
Mice, Inbred C57BL
Mice, Knockout, ApoE
Myocytes, Smooth Muscle metabolism
Myocytes, Smooth Muscle pathology
Neutrophil Infiltration
Neutrophils pathology
Plaque, Atherosclerotic
Polymorphism, Single Nucleotide
Proteins genetics
Calcium-Binding Proteins metabolism
Cell Adhesion Molecules metabolism
Coronary Artery Disease metabolism
Coronary Vessels metabolism
Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1435-1803
- Volume :
- 115
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Basic research in cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 33185739
- Full Text :
- https://doi.org/10.1007/s00395-020-00828-6