Kai Li1, Yan Li2, Youjia Yu1, Jingjing Ding1, Huijie Huang1, Chunyan Chu1, Li Hu1, Yanfang Yu1, Yue Cao1, Peng Xu1, David Fulton3, Feng Chen4,5. 1. Department of Forensic Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, People's Republic of China. 2. Department of Forensic Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, People's Republic of China. liyan_njmu@163.com. 3. Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia. 4. Department of Forensic Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, People's Republic of China. fchen@njmu.edu.cn. 5. Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, People's Republic of China. fchen@njmu.edu.cn.
Abstract
OBJECTIVES: Pulmonary hypertension (PH) is a life-threatening progressive disease with high mortality in the elderly. However, the pathogenesis of PH has not been fully understood and there is no effective therapy to reverse the disease process. This study aims to determine whether cellular senescence is involved in the development of PH. METHODS: The rat PH model was established by intraperitoneal injection of monocrotaline and evaluated by pulmonary arteriole wall thickness and right ventricular hypertrophy index. Human lung fibroblasts (HLFs) were treated with CoCl2 or hypoxia to induce cellular senescence in vitro. SA-β-gal staining and the changes of senescent markers were used to examine cellular senescence. The molecular mechanism of cellular senescence was further explored by detecting reactive oxygen species (ROS) levels and culturing cells with a conditioned medium. RESULTS: We revealed the cellular senescence of pulmonary adventitial fibroblasts in vivo in the rat PH model. The expression of Bmi-1, an important regulator of senescence, was decreased in the lungs of PH rats and localized in adventitial fibroblasts. The in vitro experiments showed that p16 expression was increased while Bmi-1 expression was decreased after CoCl2 treatment in HLFs. Mechanistically, Bmi-1 could alleviate CoCl2-induced HLFs senescence by eliminating ROS which further promoted the proliferation of pulmonary artery smooth muscle cells by paracrine mode of action of HLFs. CONCLUSION: Bmi-1 alleviates the cellular senescence of pulmonary fibroblasts in PH, which expands the pathogenesis of PH and provides a theoretical basis for targeting senescent cells in the treatment of PH.
OBJECTIVES:Pulmonary hypertension (PH) is a life-threatening progressive disease with high mortality in the elderly. However, the pathogenesis of PH has not been fully understood and there is no effective therapy to reverse the disease process. This study aims to determine whether cellular senescence is involved in the development of PH. METHODS: The ratPH model was established by intraperitoneal injection of monocrotaline and evaluated by pulmonary arteriole wall thickness and right ventricular hypertrophy index. Human lung fibroblasts (HLFs) were treated with CoCl2 or hypoxia to induce cellular senescence in vitro. SA-β-gal staining and the changes of senescent markers were used to examine cellular senescence. The molecular mechanism of cellular senescence was further explored by detecting reactive oxygen species (ROS) levels and culturing cells with a conditioned medium. RESULTS: We revealed the cellular senescence of pulmonary adventitial fibroblasts in vivo in the ratPH model. The expression of Bmi-1, an important regulator of senescence, was decreased in the lungs of PHrats and localized in adventitial fibroblasts. The in vitro experiments showed that p16 expression was increased while Bmi-1 expression was decreased after CoCl2 treatment in HLFs. Mechanistically, Bmi-1 could alleviate CoCl2-induced HLFs senescence by eliminating ROS which further promoted the proliferation of pulmonary artery smooth muscle cells by paracrine mode of action of HLFs. CONCLUSION:Bmi-1 alleviates the cellular senescence of pulmonary fibroblasts in PH, which expands the pathogenesis of PH and provides a theoretical basis for targeting senescent cells in the treatment of PH.
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