Hypoxia promotes pulmonary vascular remodeling via HIF-1α to regulate mitochondrial dynamics
Xi CHEN1
Jia-Mei YAO2
Xia FANG3
Cui ZHANG4
Yu-Shu YANG4
Cheng-Ping HU1
Qiong CHEN2
Guang-Wei ZHONG2
1.National Center for Clinical Medicine for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, China;Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China2.National Center for Clinical Medicine for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, China;Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China;International Medical Center, Xiangya Hospital, Central South University, Changsha, China3.Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China;Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China4.National Center for Clinical Medicine for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, China;Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
摘要：Background Increasing research suggests that mitochondrial defect plays a major role in pulmonary hypertension (PH) pathogenesis.Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation and apoptosis balance.However,the molecular mechanism underlying of this balance is still unknown.Methods To clarify the biological effects of hypoxic air exposure and hypoxia-inducible factor-1α (HIF-1α) on pulmonary arterial smooth muscle cell (PASMC) and pulmonary arterial hypertension rats,the cells were cultured in a hypoxic chamber under oxygen concentrations.Cell viability,reactive oxygen species level,cell death,mitochondrial morphology,mitochondrial membrane potential,mitochondrial function and mitochondrial biosynthesis,as well as fission-and fusion-related proteins,were measured under hypoxic conditions.In addition,rats were maintained under hypoxic conditions,and the right ventricular systolic pressure,right ventricular hypertrophy index and right ventricular weight/body weight ratio were examined and recorded.Further,we assessed the role of HIF-1α in the development and progression of PH using HIF-1α gene knockdown using small interfering RNA transfection.Mdivi-1 treatment was performed before hypoxia to inhibit dynamin-related protein 1 (Drp1).Results We found that HIF-1α expression was increased during hypoxia,which was crucial for hypoxia-induced mitochondrial dysfunction and hypoxia-stimulated PASMCs proliferation and apoptosis.We also found that targeting mitochondrial fission Drpl by mitochondrial division inhibitor Mdivi-1 was effective in PH model rats.The results showed that mitochondrial dynamics were involved in the pulmonary vascular remodeling under hypoxia in vivo and in vitro.Furthermore,HIF-1α also modulated mitochondrial dynamics in pulmonary vascular remodeling under hypoxia through directly regulating the expression of Drp 1.Conclusions In conclusion,our data suggests that abnormal mitochondrial dynamics could be a marker for the early diagnosis of PH and monitoring disease progression.Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in PH.
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论文发表日期：2019-12-28
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：17( 855-871 )
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