Abstract 535: Stem Cell--Mediated Atherosclerosis Plaque Repair

Objectives: Notch Signaling is known to regulate the biology of stem cells and the embryonic development of the aorta, but its role in atherosclerosis has received limited investigation. We recently reported that several Notch pathway components are activated in atherosclerotic plaques and result in endothelial inflammation and senescence. We investigate if differential Notch expression plays a role in the balance between plaque repair versus progression as a putative determinant of overall plaque burden. Methods: We assessed Notch expression in Bone Marrow Stem Cells of atherosclerosis-predisposed ApoE -/- mice (N=5) by PCRArray. We queried our data base of 1179 human blood samples (patients phenotyped by cardiac catherization and genotyped by Genome-Wide Human SNP Array) to determine if circulating mononuclear cells in patients with severe coronary artery disease (CAD) show variant genetic patterns within the family of Notch genes. Results: The Notch pathway was significantly activated in bone marrow-derived Endothelial Progenitor Cells (EPC) and Mesenchymal Stem Cells (MSC) from young ApoE -/- mice before initiation of high-fat diet and before aortic development of atherosclerosis plaque (some components such as Hes-1 and Hey-1 increased by up to 6.6- and 8.2-fold, respectively P <0.001). Genetic association analysis detected 4 SNPs with statistically significant linkage to severe CAD. Conclusions: Notch signaling may be linked to CAD risk by modulating the biology of bone marrow-derived progenitor/stem cell pools. These findings, together with our prior findings that Notch signaling is activated in atherosclerotic plaques and results in endothelial inflammation and senescence, strongly implicate the involvement of Notch in atherosclerosis pathogenesis.