MyomiR-499, Exosomes and Endothelial and Endothelial Progenitor Cells dysfunction in Diabetes

PROJECT SUMMARY/ABSTRACT Diabetes mellitus is a common chronic metabolic disease imposing great social and economic burden, and is considered as one of the major health-threats in USA and worldwide. The morbidity of critical limb ischemia (CLI) in diabetic patients is extremely high (up to 76% in some studies). Therefore, understanding the mechanisms of CLI pathogenesis in diabetes is critical for developing novel therapeutic strategies. We and others have reported that enhancing endothelial cell (EC) and endothelial progenitor cell function improves ischemic tissue repair. Recently, there is growing evidence indicating that diabetes severely impairs angiogenic property of EC/EPC that may directly limit CLI repair. The overall goal of this proposal is to elucidate the role of muscle-specific miR-499 in diabetes-impaired EC/EPC function. The premise of our proposed studies is based on our preliminary studies showing that expression of miR-499, a muscle-specific miR, was enhanced in EC/EPCs from db/db mice. Our central hypothesis is that diabetes e nhanced miR-499 impairs EC/EPCs function and ischemic limb repair via skeletal muscle-derived exosomal delivery of miR-499 to EC/EPCs. We propose to conduct complementary experiments organized under the following 3 aims: 1. Determine the role of miR-499 in diabetes-induced EC and EPC dysfunction; 2. Demonstrate the role of muscle-derived exosomes in miR-499-induced EC dysfunction in diabetes; 3. Elucidate the molecular signaling downstream of miR-499 involved in diabetes-impaired angiogenic property of EC. Our findings will provide fundamental insights into development of novel strategies for therapeutics of CLI in diabetic patients. 1