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.

• Authors: Michael J Winkler, Philipp Müller, Amin M Sharifi, Jana Wobst, Hanna Winter, Michal Mokry, Lijiang Ma, Sander W van der Laan, Shichao Pang, Benedikt Miritsch, Julia Hinterdobler, Julia Werner, Barbara Stiller, Ulrich Güldener, Tom R Webb, Folkert W Asselbergs, Johan L M Björkegren, Lars Maegdefessel, Heribert Schunkert, Hendrik B Sager, Thorsten Kessler
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 115 Issue 6 Pg. 67 (11 13 2020) ISSN: 1435-1803 [Electronic] Germany
• PMID: 33185739 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Ly
• Calcium-Binding Proteins
• Cell Adhesion Molecules
• Chemokine CXCL1
• Cxcl1 protein, mouse
• Ly-6C antigen, mouse
• Polydom protein, mouse
• Proteins
• SVEP1 protein, human

Topics

• Animals
• Antigens, Ly (metabolism)
• Calcium-Binding Proteins (deficiency, genetics, metabolism)
• Cell Adhesion Molecules (deficiency, genetics, metabolism)
• Cells, Cultured
• Chemokine CXCL1 (genetics, metabolism)
• Chemotaxis, Leukocyte
• Coronary Artery Disease (genetics, metabolism, pathology)
• Coronary Vessels (metabolism, pathology)
• Disease Models, Animal
• Endothelial Cells (metabolism, pathology)
• Genetic Association Studies
• Genetic Predisposition to Disease
• Haploinsufficiency
• Humans
• Macrophages (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout, ApoE
• Myocytes, Smooth Muscle (metabolism, pathology)
• Neutrophil Infiltration
• Neutrophils (pathology)
• Plaque, Atherosclerotic
• Polymorphism, Single Nucleotide
• Proteins (genetics, metabolism)