Hypoxia-Inducible Factor-1α in Pulmonary Artery Smooth Muscle Cells Lowers Vascular Tone by Decreasing Myosin Light Chain Phosphorylation
| Autor: | Yu-Mee Kim, David N. Cornfield, Cristina M. Alvira, Lihua Ying, Sushma Reddy, Elizabeth A. Barnes |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Myosin Light Chains Time Factors Myosin light-chain kinase Genotype Physiology Muscle Proteins Pulmonary Artery Biology Transfection Muscle Smooth Vascular Article Mice Internal medicine Hypoxic pulmonary vasoconstriction medicine.artery medicine Animals Humans Phosphorylation Hypoxia Promoter Regions Genetic Cells Cultured Mice Knockout Microfilament Proteins Middle Aged Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Pulmonary hypertension Disease Models Animal Phenotype Endocrinology Hypoxia-inducible factors Vasoconstriction Acute Disease Chronic Disease Immunology Pulmonary artery Ventricular pressure RNA Interference medicine.symptom Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation Research. 112:1230-1233 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.112.300646 |
| Popis: | Rationale: Hypoxia-inducible factor-1α (HIF-1α), an oxygen (O 2 )-sensitive transcription factor, mediates transcriptional responses to low-O 2 tension states. Although acute hypoxia causes pulmonary vasoconstriction and chronic hypoxia can cause vascular remodeling and pulmonary hypertension, conflicting data exist on the role of HIF-1α in modulating pulmonary vascular tone. Objective: To investigate the role of smooth muscle cell (SMC)–specific HIF-1α in regulating pulmonary vascular tone. Methods and Results: Mice with an SMC-specific deletion of HIF-1α (SM22α-HIF-1α −/− ) were created to test the hypothesis that pulmonary artery SMC (PASMC) HIF-1α modulates pulmonary vascular tone and the response to hypoxia. SM22α-HIF-1α −/− mice exhibited significantly higher right ventricular systolic pressure compared with wild-type littermates under normoxia and with exposure to either acute or chronic hypoxia in the absence of histological evidence of accentuated vascular remodeling. Moreover, myosin light chain phosphorylation, a determinant of SMC tone, was higher in PASMCs isolated from SM22α-HIF-1α −/− mice compared with wild-type PASMCs, during both normoxia and after acute hypoxia. Further, overexpression of HIF-1α decreased myosin light chain phosphorylation in HIF-1α–null SMCs. Conclusions: In both normoxia and hypoxia, PASMC HIF-1α maintains low pulmonary vascular tone by decreasing myosin light chain phosphorylation. Compromised PASMC HIF-1α expression may contribute to the heightened vasoconstriction that characterizes pulmonary hypertension. |
| Databáze: | OpenAIRE |
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