Yuan He1, Jian-Hua Zhong2, Xiao-Dong Wei3, Chu-Ying Huang4, Pai-Lan Peng4, Jun Yao4, Xiu-Sheng Song4, Wan-Li Fan4, Guang-Cai Li5. 1. Department of Ultrasound, the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, China. 2. Department of Neurology, the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, China. 3. Department of Thoracic and Cardiovascular Surgery, Minda Hospital of Hubei Minzu University, Enshi, 445000, China. 4. Department of Pulmonary and Critical Care Medicine, the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, China. 5. Department of Pulmonary and Critical Care Medicine, the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, China. Guangcail66@aliyun.com.
Abstract
OBJECTIVE: Pulmonary hypertension (PH) is a severe pulmonary vascular disease that eventually leads to right ventricular failure and death. The purpose of this study was to investigate the mechanism by which pachymic acid (PA) pretreatment affects PH and pulmonary vascular remodeling in rats. METHODS: PH was induced via hypoxia exposure and administration of PA (5 mg/kg per day) in male Sprague-Dawley rats. Hemodynamic parameters were measured using a right ventricular floating catheter and pulmonary vascular morphometry was measured by hematoxylin-eosin (HE), α-SMA and Masson staining. MTT assays and EdU staining were used to detect cell proliferation, and apoptosis was analyzed by TUNEL staining. Western blotting and immunohistochemistry were used to detect the expression of proteins related to the Nrf2-Keap1-ARE pathway. RESULTS: PA significantly alleviated hypoxic PH and reversed right ventricular hypertrophy and pulmonary vascular remodeling. In addition, PA effectively inhibited proliferation and promoted apoptosis in hypoxia-induced pulmonary artery smooth muscle cells (PASMCs). Moreover, PA pretreatment inhibited the expression of peroxy-related factor (MDA) and promoted the expression of antioxidant-related factors (GSH-PX and SOD). Furthermore, hypoxia inhibited the Nrf2-Keap1-ARE signaling pathway, while PA effectively activated this pathway. Most importantly, addition of the Nrf2 inhibitor ML385 reversed the inhibitory effects of PA on ROS generation, proliferation, and apoptosis tolerance in hypoxia-induced PASMCs. CONCLUSION: Our study suggests that PA may reverse PH by regulating the Nrf2-Keap1-ARE signaling pathway.
OBJECTIVE: Pulmonary hypertension (PH) is a severe pulmonary vascular disease that eventually leads to right ventricular failure and death. The purpose of this study was to investigate the mechanism by which pachymic acid (PA) pretreatment affects PH and pulmonary vascular remodeling in rats. METHODS: PH was induced via hypoxia exposure and administration of PA (5 mg/kg per day) in male Sprague-Dawley rats. Hemodynamic parameters were measured using a right ventricular floating catheter and pulmonary vascular morphometry was measured by hematoxylin-eosin (HE), α-SMA and Masson staining. MTT assays and EdU staining were used to detect cell proliferation, and apoptosis was analyzed by TUNEL staining. Western blotting and immunohistochemistry were used to detect the expression of proteins related to the Nrf2-Keap1-ARE pathway. RESULTS: PA significantly alleviated hypoxic PH and reversed right ventricular hypertrophy and pulmonary vascular remodeling. In addition, PA effectively inhibited proliferation and promoted apoptosis in hypoxia-induced pulmonary artery smooth muscle cells (PASMCs). Moreover, PA pretreatment inhibited the expression of peroxy-related factor (MDA) and promoted the expression of antioxidant-related factors (GSH-PX and SOD). Furthermore, hypoxia inhibited the Nrf2-Keap1-ARE signaling pathway, while PA effectively activated this pathway. Most importantly, addition of the Nrf2 inhibitor ML385 reversed the inhibitory effects of PA on ROS generation, proliferation, and apoptosis tolerance in hypoxia-induced PASMCs. CONCLUSION: Our study suggests that PA may reverse PH by regulating the Nrf2-Keap1-ARE signaling pathway.
Authors: Marius M Hoeper; Hossein-Ardeschir Ghofrani; Ekkehard Grünig; Hans Klose; Horst Olschewski; Stephan Rosenkranz Journal: Dtsch Arztebl Int Date: 2017-02-03 Impact factor: 5.594