title: p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice.
abstract: Chronic hypoxia induces pulmonary arterial remodeling, resulting in pulmonary hypertension and right ventricular hypertrophy. Hypoxia has been implicated as a physiological stimulus for p53 induction and hypoxia-inducible factor-1α (HIF-1α). However, the subcellular interactions between hypoxic exposure and expression of p53 and HIF-1α remain unclear. To examine the role of p53 and HIF-1α expression on hypoxia-induced pulmonary arterial remodeling, wild-type (WT) and p53 knockout (p53KO) mice were exposed to either normoxia or hypoxia for 8 wk. Following chronic hypoxia, both genotypes demonstrated elevated right ventricular pressures, right ventricular hypertrophy as measured by the ratio of the right ventricle to the left ventricle plus septum weights, and vascular remodeling. However, the right ventricular systolic pressures, the ratio of the right ventricle to the left ventricle plus septum weights, and the medial wall thickness of small vessels were significantly greater in the p53KO mice than in the WT mice. The p53KO mice had lower levels of p21 and miR34a expression, and higher levels of HIF-1α, VEGF, and PDGF expression than WT mice following chronic hypoxic exposure. This was associated with a higher proliferating cell nuclear antigen expression of pulmonary artery in p53KO mice. We conclude that p53 plays a critical role in the mitigation of hypoxia-induced small pulmonary arterial remodeling. By interacting with p21 and HIF-1α, p53 may suppress hypoxic pulmonary arterial remodeling and pulmonary arterial smooth muscle cell proliferation under hypoxia.
authors.affiliation: Third Department of Internal Medicine, University of Fukui, Fukui, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Mizuno
authors.forename: Herman J
authors.initials: HJ
authors.lastname: Bogaard
authors.forename: Donatas
authors.initials: D
authors.lastname: Kraskauskas
authors.forename: Aysar
authors.initials: A
authors.lastname: Alhussaini
authors.forename: Jose
authors.initials: J
authors.lastname: Gomez-Arroyo
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishizaki
mesh_terms: D000818:Animals; D016158:Genes, p53 / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis; D054462:p21-Activated Kinases / Q000096:biosynthesis
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases