Abstract 496: The Cardiometabolic Disease Risk Protein SVEP1 Activates AKT/mTOR By Signaling Through The Orphan Receptor PEAR1

• DOI: 10.1161/atvb.42.suppl_1.496
• Publication Date: 2022-11-30T18:57:15Z
• Authors: Jared S Elenbaas; Upasana Pudupakkam; Ved Patel; Katrina Ashworth; Chul Joo Kang; In-Hyuk Jung; Katherine Santana; Arturo Alisio; Jorge Di Paola; Nathan Stitziel
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

Background: Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that circulates in plasma causally related to cardiovascular disease, hypertension, 2 diabetes. A recent genome wide association study (GWAS) also implicates SVEP1 platelet reactivity. The gene most strongly associated with reactivity the GWAS Platelet Endothelial Cell Receptor ( PEAR1 ), a encodes orphan receptor tyrosine kinase-like associates disease. Little known about molecular interactions disease mechanisms of these proteins, despite their associations Methods: We used Mendelian Randomization (MR) phenome-wide studies identify candidate interactions. tested using recombinant proteins molecular, cellular, ex vivo assays. Results: coding variant within ectodomain alters levels humans (p=1.7x10^-17), suggesting may interact. MR demonstrates genetically determined, increased associate decreased (p=1.3x10^-11), further supporting interaction. co-immunoprecipitates SVEP1. Exposure induces phosphorylation activation AKT/mTOR signaling endothelial cells, vascular smooth muscle platelets. siRNA knockdown abrogates this signaling. cells adhere proliferate response immobilized Platelets isolated from mice lacking have lower relative controls phenocopy platelets PEAR1. Conclusions: Despite robust evidence for role critical gaps remain our understanding mechanisms. Here, we as first biological ligand potent activator interaction between particularly intriguing, given prominent disrupting be therapeutically beneficial.