Regulation of Hypoxia-induced Pulmonary Hypertension by Vascular Smooth Muscle Hypoxia-Inducible Factor-1α

被引:225
作者
Ball, Molly K. [1 ]
Waypa, Gregory B. [1 ]
Mungai, Paul T. [1 ]
Nielsen, Jacqueline M. [1 ]
Czech, Lyubov [1 ]
Dudley, V. Joseph [1 ]
Beussink, Lauren [2 ]
Dettman, Robert W. [1 ]
Berkelhamer, Sara K. [1 ]
Steinhorn, Robin H. [1 ]
Shah, Sanjiv J. [2 ]
Schumacker, Paul T. [1 ,2 ]
机构
[1] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA
[2] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA
基金
美国国家卫生研究院;
关键词
pulmonary circulation; right ventricular hypertrophy; animal disease models; knock-out mice; MICE PARTIALLY DEFICIENT; CELL-PROLIFERATION; ADVENTITIAL FIBROBLASTS; INTERMITTENT HYPOXIA; GENE-EXPRESSION; HEART-FAILURE; GROWTH-FACTOR; ARTERY; RESPONSES; RATS;
D O I
10.1164/rccm.201302-0302OC
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Rationale: Chronic hypoxia induces pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy. At present, little is known about mechanisms driving these responses. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a master regulator of transcription in hypoxic cells, up-regulating genes involved in energy metabolism, proliferation, and extracellular matrix reorganization. Systemic loss of a single HIF-1 alpha allele has been shown to attenuate hypoxic pulmonary hypertension, but the cells contributing to this response have not been identified. Objectives: We sought to determine the contribution of HIF-1 alpha in smooth muscle on pulmonary vascular and right heart responses to chronic hypoxia. Methods: We used mice with homozygous conditional deletion of HIF-1 alpha combined with tamoxifen-inducible smooth muscle-specific Cre recombinase expression. Mice received either tamoxifen or vehicle followed by exposure to either normoxia or chronic hypoxia (10% O-2) for 30 days before measurement of cardiopulmonary responses. Measurements and Main Results: Tamoxifen-induced smooth muscle-specific deletion of HIF-1 alpha attenuated pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, right ventricular hypertrophy was unchanged despite attenuated pulmonary pressures. Conclusions: These results indicate that HIF-1 alpha in smooth muscle contributes to pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, loss of HIF-1 function in smooth muscle does not affect hypoxic cardiac remodeling, suggesting that the cardiac hypertrophy response is not directly coupled to the increase in pulmonary artery pressure.
引用
收藏
页码:314 / 324
页数:11
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