SVEP1 is an endogenous ligand for the orphan receptor PEAR1.
Jared S ElenbaasUpasana PudupakkamKatrina J AshworthChul Joo KangVed PatelKatherine SantanaIn-Hyuk JungPaul C LeeKendall H BurksJunedh M AmruteRobert P MechamCarmen M HalabiArturo AlisoJorge Di PaolaNathan O StitzielPublished in: Nature communications (2023)
Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that causally promotes vascular disease and associates with platelet reactivity in humans. Here, using a human genomic and proteomic approach, we identify a high affinity, disease-relevant, and potentially targetable interaction between SVEP1 and the orphan receptor Platelet and Endothelial Aggregation Receptor 1 (PEAR1). This interaction promotes PEAR1 phosphorylation and disease associated AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 have reduced platelet activation, and exogenous SVEP1 induces PEAR1-dependent activation of platelets. SVEP1 and PEAR1 causally and concordantly relate to platelet phenotypes and cardiovascular disease in humans, as determined by Mendelian Randomization. Targeting this receptor-ligand interaction may be a viable therapeutic strategy to treat or prevent cardiovascular and thrombotic disease.
Keyphrases
- cardiovascular disease
- extracellular matrix
- endothelial cells
- cell proliferation
- signaling pathway
- type diabetes
- induced apoptosis
- oxidative stress
- small molecule
- dna methylation
- metabolic syndrome
- copy number
- high fat diet induced
- protein protein
- protein kinase
- induced pluripotent stem cells
- pluripotent stem cells