Tian-Tian Zhu1, Wei-Fang Zhang2, Ping Luo3, Zhao-Xin Qian4, Feng Li5, Zheng Zhang6, Chang-Ping Hu7. 1. Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China. 2. Department of Pharmacy, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China. 3. Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. 4. Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. 5. Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China. 6. Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China. Electronic address: zzhang@csu.edu.cn. 7. Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China. Electronic address: huchangping@csu.edu.cn.
Abstract
AIM: Chronic hypoxia leads to right ventricular hypertrophy (RVH). RVH is believed to result from hypoxia-induced pulmonary hypertension. However, if hypoxia impacts RVH directly awaits clarification. Hypoxia triggers oxidative stress, and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mediates reactive oxygen species (ROS) generation in different cells. Therefore, this study aims to explore whether LOX-1-mediated oxidative stress accounts for hypoxia-induced RVH. MAIN METHODS: Rats developed RVH after 3weeks of hypoxia (10% O2). Immunofluorescence staining was performed to evaluate H9C2 cell hypertrophy induced by hypoxia (3% O2). Real-time PCR and Western-blot were performed to assess LOX-1, NADPH oxidases (NOX), collagen I/III, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) expression. DCFH-DA staining was performed to measure ROS generation. KEY FINDINGS: Hypoxia induced RVH and cardiac fibrosis in rats, as indicated by enlarged cardiomyocytes and deposition of extracellular matrix. Interestingly, hypoxia treatment directly induced H9C2 cardiomyocyte hypertrophy, implying direct effects of hypoxia on cell hypertrophy. Rat and H9C2 hypertrophy model revealed that cell hypertrophy was accompanied by marked increase in LOX-1 expression. Knockdown of LOX-1 significantly ameliorated H9C2 cell hypertrophy. Mechanistically, hypoxia induced prominent oxidative stress in rat right ventricles and H9C2 cells, most likely as a result from increased expression of NOX2/4, contributing to RVH. Knockdown of LOX-1 significantly attenuated H9C2 cell oxidative stress, with a concomitant decrease in NOX2/4 expression. SIGNIFICANCE: LOX-1/NOX/ROS pathway could represent a novel mechanism underlying hypoxia-induced RVH. Therapeutic targeting of LOX-1 would be exploited to treat RVH owing to chronic hypoxia exposure.
AIM: Chronic hypoxia leads to right ventricular hypertrophy (RVH). RVH is believed to result from hypoxia-induced pulmonary hypertension. However, if hypoxia impacts RVH directly awaits clarification. Hypoxia triggers oxidative stress, and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mediates reactive oxygen species (ROS) generation in different cells. Therefore, this study aims to explore whether LOX-1-mediated oxidative stress accounts for hypoxia-induced RVH. MAIN METHODS:Rats developed RVH after 3weeks of hypoxia (10% O2). Immunofluorescence staining was performed to evaluate H9C2 cell hypertrophy induced by hypoxia (3% O2). Real-time PCR and Western-blot were performed to assess LOX-1, NADPH oxidases (NOX), collagen I/III, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) expression. DCFH-DA staining was performed to measure ROS generation. KEY FINDINGS:Hypoxia induced RVH and cardiac fibrosis in rats, as indicated by enlarged cardiomyocytes and deposition of extracellular matrix. Interestingly, hypoxia treatment directly induced H9C2 cardiomyocyte hypertrophy, implying direct effects of hypoxia on cell hypertrophy. Rat and H9C2 hypertrophy model revealed that cell hypertrophy was accompanied by marked increase in LOX-1 expression. Knockdown of LOX-1 significantly ameliorated H9C2 cell hypertrophy. Mechanistically, hypoxia induced prominent oxidative stress in rat right ventricles and H9C2 cells, most likely as a result from increased expression of NOX2/4, contributing to RVH. Knockdown of LOX-1 significantly attenuated H9C2 cell oxidative stress, with a concomitant decrease in NOX2/4 expression. SIGNIFICANCE: LOX-1/NOX/ROS pathway could represent a novel mechanism underlying hypoxia-induced RVH. Therapeutic targeting of LOX-1 would be exploited to treat RVH owing to chronic hypoxia exposure.
Authors: Eduardo Pena; Patricia Siques; Julio Brito; Silvia M Arribas; Rainer Böger; Juliane Hannemann; Fabiola León-Velarde; M Carmen González; M Rosario López; Ángel Luis López de Pablo Journal: Int J Mol Sci Date: 2020-11-13 Impact factor: 5.923