What is the clinical evidence from this study?

Study design: Other. Population: Atherosclerosis. Intervention: Svep1 haploinsufficiency vs. Svep1 wild-type. Primary outcome: Atherosclerotic plaque burden (10^3 µm^2) (p=0.01).

November 13, 2020Open Access

Functional investigation of the coronary artery disease gene SVEP1

Key Result

Svep1 haploinsufficiency increased atherosclerotic plaque size and enhanced recruitment of proinflammatory leukocytes to the vascular wall in atherosclerosis-prone mice.

Structured PICO

Does SVEP1 deficiency or missense mutation increase atherosclerotic plaque formation and vascular inflammation?

Population

Translational study investigating the functional role of the SVEP1 gene in atherosclerosis using human vascular tissues, primary cells, and an ApoE-/- mouse model.

Exposure

SVEP1 deficiency (Svep1 haploinsufficiency in mice) or SVEP1 missense variant (p.D2702G)

Comparator

Wild-type SVEP1 (Svep1+/+ in mice)

Outcome

Atherosclerotic plaque size and vascular inflammation (leukocyte recruitment, CXCL1 expression)surrogate

SVEP1 plays an atheroprotective role, and its deficiency or missense mutation promotes endothelial CXCL1 expression, leukocyte recruitment, and atherosclerotic plaque progression.

Main Result

Absolute Event Rate: 411.8% vs 325.1%

p-value: p=0.01

Limitations

The molecular mechanisms by which SVEP1 mediates its effects on endothelial cells remain unknown.
A heterozygous knockout of Svep1 might not fully replicate the effects of the human risk variant.
In vitro experiments lack the natural extracellular matrix environment and may not fully reflect in vivo situations.

Abstract

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, 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.

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