SVEP1 is a human coronary artery disease locus that promotes atherosclerosis
| Autor: | Erica P. Young, Robert P. Mecham, Puja Kachroo, In Hyuk Jung, Katherine Santana, Arturo Alisio, Jared S. Elenbaas, Kory J. Lavine, Babak Razani, Chul Joo Kang, Nathan O. Stitziel |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Vascular smooth muscle Myocytes Smooth Muscle Integrin Notch signaling pathway Inflammation Coronary Artery Disease 030204 cardiovascular system & hematology Muscle Smooth Vascular Article Coronary artery disease Extracellular matrix Mice 03 medical and health sciences 0302 clinical medicine Von Willebrand factor Animals Humans Medicine Cells Cultured Cell Proliferation biology business.industry General Medicine Atherosclerosis medicine.disease Plaque Atherosclerotic Mice Inbred C57BL 030104 developmental biology Fibroblast growth factor receptor biology.protein Cancer research medicine.symptom business Cell Adhesion Molecules |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | 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. Taken together, our results suggest that VSMC-derived SVEP1 is a pro-atherogenic factor, and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans. |
| Databáze: | OpenAIRE |
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