Research ArticleAtherosclerosis

SVEP1 is a human coronary artery disease locus that promotes atherosclerosis

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Science Translational Medicine  24 Mar 2021:
Vol. 13, Issue 586, eabe0357
DOI: 10.1126/scitranslmed.abe0357

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Probing plaque pathogenesis

Genetic variants linked to cardiometabolic disease can help identify targets for therapies. An SVEP1 mutation had previously been associated with coronary artery disease, and here, Jung et al. studied the role of this extracellular matrix protein in atherosclerosis. SVEP1 was expressed by vascular smooth muscle cells in human tissue samples from patients with atherosclerosis and was up-regulated in a mouse model of atherosclerosis. SVEP1 induced proliferation and differentiation of smooth muscle cells and promoted inflammation in plaques. Results suggest that targeting SVEP1 could protect against atherosclerosis.

Abstract

A low-frequency variant of sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SVEP1), an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, if and how SVEP1 might contribute to atherosclerosis remained unclear. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice and is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1 and is further increased by the coronary disease–associated SVEP1 variant p.D2702G. These effects ultimately drive inflammation and promote atherosclerosis. Together, our results suggest that VSMC-derived SVEP1 is a proatherogenic factor and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.

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