Bi Deng1, Jie Du2, Rong Hu2, Ai-Ping Wang2, Wei-Hua Wu3, Chang-Ping Hu2, Yuan-Jian Li2, Xiao-Hui Li4. 1. Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha 410078, China; The Guangxi Zhuang Autonomous Region People's Hospital, Xining 530021, China. 2. Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha 410078, China. 3. Department of Pharmaceutical Sciences, Hunan University of Medical, Huaihua 418000, China. 4. Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha 410078, China. Electronic address: xiaohuili@csu.edu.cn.
Abstract
AIMS: Activation of hypoxia inducible factor-1 (HIF) is a hallmark in hypoxia-induced pulmonary hypertension (HPH). microRNAs play a significant role in regulating proliferation of pulmonary arterial smooth muscle cells (PASMCs) in pulmonary hypertension. Previous studies have shown that HIF-1β is a target of miR-103/107. In this present study, we aimed to investigate whether miR-103/107 regulate vascular remodeling in HPH via HIF-1β. MAIN METHODS: The HPH model was built by hypoxia exposure in rats. Real-time PCR and Western blotting were used to determine the expression of miR-103/107 and HIF-1β. Proliferation of PASMCs was examined by 5-bromo-2'-deoxyuridine (BrdU) incorporation method. The functions of miR-103/107 on PASMCs proliferation, HIF-1α and HIF-1β expression were assessed by transfecting miR-103/107 mimics and inhibitors. KEY FINDINGS: Significant down-regulation of miR-103/107 was observed in remodeled intrapulmonary vascular in HPH rats and hypoxia-exposured PASMCs, whereas HIF-1α and HIF-1β expression were up-regulated. Hypoxia exposure induced significant proliferation of PASMCs, overexpression of miR-103/107 inhibited but miR-103/107 inhibitors exacerbated PASMCs proliferation. Gain-of-function and loss-of-function experiments showed that miR-103/107 expression was inversely correlated with HIF-1β level. No significant changes of HIF-1α expression were observed under miR-103/107 mimic treatment. SIGNIFICANCE: Loss of suppression on HIF-1β by miR-103/107 may contribute to excess proliferation of PASMCs and vascular remodeling in hypoxic pulmonary hypertension.
AIMS: Activation of hypoxia inducible factor-1 (HIF) is a hallmark in hypoxia-induced pulmonary hypertension (HPH). microRNAs play a significant role in regulating proliferation of pulmonary arterial smooth muscle cells (PASMCs) in pulmonary hypertension. Previous studies have shown that HIF-1β is a target of miR-103/107. In this present study, we aimed to investigate whether miR-103/107 regulate vascular remodeling in HPH via HIF-1β. MAIN METHODS: The HPH model was built by hypoxia exposure in rats. Real-time PCR and Western blotting were used to determine the expression of miR-103/107 and HIF-1β. Proliferation of PASMCs was examined by 5-bromo-2'-deoxyuridine (BrdU) incorporation method. The functions of miR-103/107 on PASMCs proliferation, HIF-1α and HIF-1β expression were assessed by transfecting miR-103/107 mimics and inhibitors. KEY FINDINGS: Significant down-regulation of miR-103/107 was observed in remodeled intrapulmonary vascular in HPH rats and hypoxia-exposured PASMCs, whereas HIF-1α and HIF-1β expression were up-regulated. Hypoxia exposure induced significant proliferation of PASMCs, overexpression of miR-103/107 inhibited but miR-103/107 inhibitors exacerbated PASMCs proliferation. Gain-of-function and loss-of-function experiments showed that miR-103/107 expression was inversely correlated with HIF-1β level. No significant changes of HIF-1α expression were observed under miR-103/107 mimic treatment. SIGNIFICANCE: Loss of suppression on HIF-1β by miR-103/107 may contribute to excess proliferation of PASMCs and vascular remodeling in hypoxic pulmonary hypertension.