Increased expression of microRNA-221 inhibits PAK1 in endothelial progenitor cells and impairs its function via c-Raf/MEK/ERK pathway |
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| Affiliation: | 1. Department of Nuclear Medicine, Shanghai 10th People’s Hospital, Tongji University School of Medicine, Shanghai 200072, PR China;2. Department of Gastrointestinal Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, PR China;3. Department of Anatomy & neurobiology, School of Medicine, Tongji University, Shanghai 200072, PR China;1. Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, P.O. Box 9502, 2300RA Leiden, The Netherlands;2. Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands;3. Merck Research Laboratories, Newhouse, UK;4. Merck Research Laboratories, Oss, The Netherlands;1. Department of Cell Biology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, China;2. Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, China;3. State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, Changchun, 130012, China;1. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, United States;2. Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, United States;3. North Carolina Jaycee Burn Center, Department of Surgery, University of North Carolina, Chapel Hill, NC 27599, United States |
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| Abstract: | Coronary artery disease (CAD) is associated with high mortality and occurs via endothelial injury. Endothelial progenitor cells (EPCs) restore the integrity of the endothelium and protect it from atherosclerosis. In this study, we compared the expression of microRNAs (miRNAs) in EPCs in atherosclerosis patients and normal controls. We found that miR-221 expression was significantly up-regulated in patients compared with controls. We predicted and identified p21/Cdc42/Rac1-activated kinase 1 (PAK1) as a novel target of miR-221 in EPCs. We also demonstrated that miR-221 targeted a putative binding site in the 3′UTR of PAK1, and absence of this site was inversely associated with miR-221 expression in EPCs. We confirmed this relationship using a luciferase reporter assay. Furthermore, overexpression of miR-221 in EPCs significantly decreased EPC proliferation, in accordance with the inhibitory effects induced by decreased PAK1. Overall, these findings demonstrate that miR-221 affects the MEK/ERK pathway by targeting PAK1 to inhibit the proliferation of EPCs. |
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