Abstract
Platelet Endothelial Aggregation Receptor 1 (PEAR1) is a newly identified membrane protein reported to be involved in multiple vascular and thrombotic processes. While most studies to date have focused on the effects of this receptor in platelets, PEAR1 is located in multiple tissues including the endothelium, where it is most highly expressed. Our first objective was to evaluate the role of PEAR1 in endothelial function by examining flow-mediated dilation of the brachial artery in 641 participants from the Heredity and Phenotype Intervention Heart Study. Our second objective was to further define the impact of PEAR1 on cardiovascular disease computationally through meta-analysis of 75,000 microarrays, yielding insights regarding PEAR1 function, and predictions of phenotypes and diseases affected by PEAR1 dysregulation. Based on the results of this meta-analysis we examined whether genetic variation in PEAR1 influences endothelial function using an ex vivo assay of endothelial cell migration. We observed a significant association between rs12041331 and flow-mediated dilation in participants of the Heredity and Phenotype Intervention Heart Study (P = 0.02). Meta-analysis results revealed that PEAR1 expression is highly correlated with several genes (e.g. ANG2, ACVRL1, ENG) and phenotypes (e.g. endothelial cell migration, angiogenesis) that are integral to endothelial function. Functional validation of these results revealed that PEAR1 rs12041331 is significantly associated with endothelial migration (P = 0.04). Our results suggest for the first time that genetic variation of PEAR1 is a significant determinant of endothelial function through pathways implicated in cardiovascular disease.
Highlights
Platelet endothelial aggregation receptor 1 (PEAR1; known as JEDI and MEGF12) is a recently identified transmembrane receptor expressed in a number of different tissues, with highest expression in endothelial cells and megakaryocytes [1]
We evaluated the effect of PEAR1 rs12041331 on in vivo endothelial function in 641 subjects of the Heredity and Phenotype Intervention (HAPI) Heart Study
Several subsequent studies, including our own [10], have focused almost exclusively on the functional or phenotypic effects of this gene in platelets and megakaryocytes [1,2,3, 5,6,7,8,9, 11]. These investigations have yielded insights into the molecular signaling of PEAR1 as a tyrosine kinase that signals through PI3K and Akt [1, 2], as well as the role of this receptor in megakaryopoiesis [3], platelet aggregation [1, 2, 5,6,7,8,9,10,11], antiplatelet therapy response [8,9,10,11], and cardiovascular events [10]
Summary
Platelet endothelial aggregation receptor 1 (PEAR1; known as JEDI and MEGF12) is a recently identified transmembrane receptor expressed in a number of different tissues, with highest expression in endothelial cells and megakaryocytes [1]. While little is currently known regarding the molecular mechanism(s) of this receptor, prior investigations suggest that PEAR1 is important in a diverse range of biological functions, including sustained platelet aggregation through glycoprotein αIIbβ3 [2], altered megakaryopoiesis and thrombopoiesis via PI3K/PTEN pathways [3], and apoptotic neuron clearance through endocytosis-dependent activities in dorsal root ganglia [4]. In addition to these mechanism-based investigations, several studies have examined the role of genetic variation in PEAR1, most notably the intronic single nucleotide polymorphism (SNP) rs12041331. Based on our meta-analysis’s results, we extended our findings by evaluating and confirming the effect of the PEAR1 rs12041331 variant on endothelial cell migration using functional ex vivo assays of human umbilical vein endothelial cells (HUVECs) derived from de-identified umbilical cords
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