Ling-Ping Zhu1, Ji-Peng Zhou1, Jia-Xiong Zhang1, Jun-Yao Wang1, Zhen-Yu Wang1, Miao Pan1, Ling-Fang Li1, Chuan-Chang Li1, Kang-Kai Wang1, Yong-Ping Bai1, Guo-Gang Zhang2. 1. 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.). 2. 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.
Abstract
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311