Zhu Tian-Tian, Zhang Wei-Fang, Luo Ping, Qian Zhao-Xin, Li Feng, Zhang Zheng, Hu Chang-Ping
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China.
Department of Pharmacy, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
Life Sci. 2017 Apr 1;174:35-42. doi: 10.1016/j.lfs.2017.02.016. Epub 2017 Mar 1.
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.
Rats developed RVH after 3weeks of hypoxia (10% O). Immunofluorescence staining was performed to evaluate H9C2 cell hypertrophy induced by hypoxia (3% O). 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.
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.
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.
慢性缺氧会导致右心室肥厚（RVH）。右心室肥厚被认为是由缺氧诱导的肺动脉高压所致。然而，缺氧是否直接影响右心室肥厚仍有待阐明。缺氧会引发氧化应激，而凝集素样氧化低密度脂蛋白受体-1（LOX-1）在不同细胞中介导活性氧（ROS）的生成。因此，本研究旨在探讨LOX-1介导的氧化应激是否是缺氧诱导右心室肥厚的原因。
大鼠在缺氧（10%氧气）3周后出现右心室肥厚。进行免疫荧光染色以评估缺氧（3%氧气）诱导的H9C2细胞肥大。采用实时聚合酶链反应（PCR）和蛋白质免疫印迹法（Western-blot）评估LOX-1、烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）、I/III型胶原蛋白、心钠素（ANP）和B型利钠肽（BNP）的表达。进行2',7'-二氯二氢荧光素二乙酸酯（DCFH-DA）染色以测量ROS的生成。
缺氧导致大鼠右心室肥厚和心脏纤维化，表现为心肌细胞增大和细胞外基质沉积。有趣的是，缺氧处理直接诱导H9C2心肌细胞肥大，这意味着缺氧对细胞肥大有直接影响。大鼠和H9C2肥大模型显示，细胞肥大伴随着LOX-1表达的显著增加。敲低LOX-1可显著改善H9C2细胞肥大。从机制上讲，缺氧在大鼠右心室和H9C2细胞中诱导了显著的氧化应激，这很可能是由于NOX2/4表达增加所致，从而导致右心室肥厚。敲低LOX-1可显著减轻H9C2细胞的氧化应激，同时NOX2/4表达降低。
LOX-1/NOX/ROS途径可能是缺氧诱导右心室肥厚的一种新机制。鉴于长期缺氧暴露会导致右心室肥厚，可通过靶向治疗LOX-1来治疗右心室肥厚。
