Functional investigation of the coronary artery disease gene SVEP1.
Michael J WinklerPhilipp MüllerAmin M SharifiJana WobstHanna WinterMichal MokryLijiang MaSander W van der LaanShichao PangBenedikt MiritschJulia HinterdoblerJulia WernerBarbara StillerUlrich GüldenerTom R WebbFolkert W AsselbergsJohan L M BjörkegrenLars MaegdefesselHeribert SchunkertHendrik B SagerThorsten KesslerPublished in: Basic research in cardiology (2020)
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.
Keyphrases
- wild type
- coronary artery disease
- endothelial cells
- genome wide
- cognitive decline
- high fat diet
- peripheral blood
- vascular smooth muscle cells
- poor prognosis
- percutaneous coronary intervention
- cardiovascular events
- cardiovascular disease
- intellectual disability
- dna methylation
- binding protein
- coronary artery bypass grafting
- heart failure
- type diabetes
- angiotensin ii
- insulin resistance
- metabolic syndrome
- copy number
- skeletal muscle
- long non coding rna
- acute coronary syndrome
- small molecule
- high glucose
- immune response
- transcription factor
- mild cognitive impairment
- single cell
- dendritic cells
- aortic valve
- case control