title: MiR-15b-5p Regulates Collateral Artery Formation by Targeting AKT3 (Protein Kinase B-3).
abstract: To identify circulating microRNAs that are differentially expressed in severe coronary heart disease with well or poorly developed collateral arteries and to investigate their mechanisms of action in vivo and in vitro.
  
  
  
  In our study, we identified a circulating microRNA, miR-15b-5p, with low expression that, nevertheless, characterized patients with sufficient coronary collateral artery function. Moreover, in murine hindlimb ischemia model, in situ hybridization identified that miR-15b-5p was specifically expressed in vascular endothelial cells of adductors in sham group and was remarkably downregulated after femoral artery ligation. Overexpressed miR-15b-5p significantly inhibited arteriogenesis and angiogenesis in mice. In vitro, both under basal and vascular endothelial growth factor stimulation, loss-of-function or gain-of-function studies suggested that miR-15b-5p significantly promoted or depressed the migration and proliferation of endothelial cells. We identified AKT3 (protein kinase B-3) as a direct target of miR-15b-5p. Interestingly, AKT3 deficiency by injection with Chol-AKT3-siRNA obviously suppressed arteriogenesis and the recovery of blood perfusion after femoral ligation in mice.
  
  
  
  These results indicate that circulating miR-15b-5p is a suitable biomarker for discriminating between patients with well-developed or poorly developed collaterals. Moreover, miR-15b-5p is a key regulator of arteriogenesis and angiogenesis, which may represent a potential therapeutic target for ischemic disease.
authors.affiliation: From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.).
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Zhu
authors.affiliation: From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.).
authors.forename: Ji-Peng
authors.initials: JP
authors.lastname: Zhou
authors.affiliation: From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.).
authors.forename: Jia-Xiong
authors.initials: JX
authors.lastname: Zhang
authors.affiliation: From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.).
authors.forename: Jun-Yao
authors.initials: JY
authors.lastname: Wang
authors.affiliation: From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.).
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.).
authors.forename: Miao
authors.initials: M
authors.lastname: Pan
authors.affiliation: From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.).
authors.forename: Ling-Fang
authors.initials: LF
authors.lastname: Li
authors.affiliation: From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.).
authors.forename: Chuan-Chang
authors.initials: CC
authors.lastname: Li
authors.affiliation: From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.).
authors.forename: Kang-Kai
authors.initials: KK
authors.lastname: Wang
authors.affiliation: From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.).
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Bai
authors.affiliation: From the Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China (L.-P.Z., J.-P.Z., J.-Y.W., Z.-Y.W., M.P., L.-F.L., L.C., G.-G.Z.); Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China (J.-X.Z., C.-C.L., Y.-P.B.); and Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China (K.-K.W.). xyzgg2006@sina.com baiyongping200613@163.com.
authors.forename: Guo-Gang
authors.initials: GG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003097:Collateral Circulation; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D006614:Hindlimb; D006801:Humans; D007511:Ischemia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection
chemical_list: C505361:MIRN15 microRNA, human; D035683:MicroRNAs; C570833:Mirn15 microRNA, mouse; C491754:AKT3 protein, human; C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT3; arteriogenesis; collateral circulation; hindlimb ischemia; miR-15b-5p