title: KLF5 mediates vascular remodeling via HIF-1α in hypoxic pulmonary hypertension.
abstract: Hypoxic pulmonary hypertension (HPH) is characterized by active vasoconstriction and profound vascular remodeling. KLF5, a zinc-finger transcription factor, is involved in the excessive proliferation and apoptotic resistance phenotype associated with monocrotaline-induced pulmonary hypertension. However, the molecular mechanisms of KLF5-mediated pathogenesis of HPH are largely undefined. Adult male Sprague-Dawley rats were exposed to normoxia or hypoxia (10% O2) for 4 wk. Hypoxic rats developed pulmonary arterial remodeling and right ventricular hypertrophy with significantly increased right ventricular systolic pressure. The levels of KLF5 and hypoxia-inducible factor-1α (HIF-1α) were upregulated in distal pulmonary arterial smooth muscle from hypoxic rats. The knockdown of KLF5 via short-hairpin RNA attenuated chronic hypoxia-induced hemodynamic and histological changes in rats. The silencing of either KLF5 or HIF-1α prevented hypoxia-induced (5%) proliferation and migration and promoted apoptosis in human pulmonary artery smooth muscle cells. KLF5 was immunoprecipitated with HIF-1α under hypoxia and acted as an upstream regulator of HIF-1α. The cell cycle regulators cyclin B1 and cyclin D1 and apoptosis-related proteins including bax, bcl-2, survivin, caspase-3, and caspase-9, were involved in the regulation of KLF5/HIF-1α-mediated cell survival. This study demonstrated that KLF5 plays a crucial role in hypoxia-induced vascular remodeling in an HIF-1α-dependent manner and provided a better understanding of the pathogenesis of HPH.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Pulmonary Diseases, National Ministry of Health of the People's Republic of China.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Pulmonary Diseases, National Ministry of Health of the People's Republic of China.
authors.forename: Yuanzhou
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Pulmonary Diseases, National Ministry of Health of the People's Republic of China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Pulmonary Diseases, National Ministry of Health of the People's Republic of China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Pulmonary Diseases, National Ministry of Health of the People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Pulmonary Diseases, National Ministry of Health of the People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Pulmonary Diseases, National Ministry of Health of the People's Republic of China doctorliu69@126.com.
authors.forename: Xiansheng
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C492215:Klf5 protein, rat; D051741:Kruppel-Like Transcription Factors
keywords: KLF5; hypoxia; hypoxia-inducible factor-1α; migration; survival