Exosome derived from NAMPT-Overexpressed Mesenchymal Stem Cell Improves Aortic Valve Stenosis Outcome via Downregulation of miR-146a-3P Expression

Abstract ID 93257 Poster Board 464 Objective: We previously reported that deleting CXCR4 in endothelial cells leads to aortic valve stenosis (AVS). There is no pharmacotherapy available to treat or attenuate AVS. Nicotinamide Phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway. Extracellular NAMPT is exclusively carried by exosomes in the circulation and gets internalized in distant tissues. In this study, we tested the therapeutic effects of exosome derived from NAMPT-overexpressed mouse mesenchymal stem cell (MSC) on AVS in CXCR4 endothelial cell-specific knockout mice (EC CXCR4 KO), and whether microRNA dysregulation plays a role in the stenosis progression. Methods: Echocardiography was used to confirm the presence of AVS in 6 weeks old EC CXCR4 KO mice. The mice were then randomly divided into three groups (n=5). AVS mice were injected intraperitoneally with 100 ug of exosomes derived from either NAMPT-overexpressed MSCs, regular MSCs, or PBS once a week for three consecutive weeks. The expression of miRNAs (miR-146a-3P, miR-146a-5P, miR-125b-5P, and miR-142a-5P) was measured by qPCR in the cardiac endothelial cell of control (CXCR4fl/fl), AVS and exosome-treated AVS mice. Aortic valves were stained using Alizarin Red to detect calcification, and the percentage of calcification was compared between different groups. Results: Treatment with exosome derived from NAMPT-overexpressed MSC significantly improved ejection fraction and reduced aortic valve (AV) peak velocity, AV peak pressure gradient, left ventricular internal dimension (LVID), and microcalcifications in AVS (EC CXCR4 KO) mice compared to those treated with PBS. Regular MSC-derived exosomes also showed a beneficial effect but were not statistically significant. Compared with the CXCR4fl/fl control mice, the expression of miR-146a-3P and miR-142a-5P in cardiac endothelial cells was significantly increased in mice with AVS, and exosome treatment showed a significant reduction of miR-146-3P expression. Conclusions: Our data suggest that exosomes derived from NAMPT-overexpressing MSCs may improve the outcome of aortic valve stenosis, and miR-146a-3P might play an important role in the disease development and progression.