Loss of smooth muscle cell hypoxia inducible factor‐1α underlies increased vascular contractility in pulmonary hypertension

• Published in: The FASEB journal 2017-02, Vol.31 (2), p.650-662
• Main Authors: Barnes, Elizabeth A., Chen, Chih‐Hsin, Sedan, Oshra, Cornfield, David N.
• Format: Article
• Language: English
• Subjects: Amino Acids, Dicarboxylic - pharmacology; Cell culture; Cofactors; Contraction; Dimethyl Sulfoxide - pharmacology; Disease control; Endothelial cells; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Humans; Hypertension; Hypertension, Pulmonary - metabolism; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Medical treatment; MLCK; Muscle contraction; Muscles; Myocytes, Smooth Muscle - metabolism; Myosin; Myosin-light-chain kinase; PAH; Patients; Phosphorylation; pMLC; Potassium channels (voltage-gated); Prolyl hydroxylase; prolyl hydroxylase domain; Prolyl Hydroxylases - genetics; Prolyl Hydroxylases - metabolism; Pulmonary arteries; Pulmonary artery; Pulmonary Artery - physiology; Pulmonary hypertension; Smooth muscle; Tissues; vasoconstriction; Vasoconstriction - physiology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201600557R

ABSTRACT Pulmonary arterial hypertension (PAH) is an often fatal disease with limited treatment options. Whereas current data support the notion that, in pulmonary artery endothelial cells (PAECs), expression of transcription factor hypoxia inducible factor‐1a (HIF‐1a) is increased, the role of HIF‐1a in pulmonary artery smooth muscle cells (PASMCs) remains controversial. This study investigates the hypothesis that, in PASMCs from patients with PAH, decreases in HIF‐1a expression and activity underlie augmented pulmonary vascular contractility. PASMCs and tissues were isolated from nonhypertensive control patients and patients with PAH. Compared with controls, HIF‐1a and Kv1.5 protein expression were decreased in PAH smooth muscle cells (primary culture). Myosin light chain (MLC) phosphorylation and MLC kinase (MLCK) activity‐major determinants of vascular tone‐were increased in patients with PAH. Cofactors involved in prolyl hydroxylase domain activity were increased in PAH smooth muscle cells. Functionally, PASMC contractility was inversely correlated with HIF‐1a activity. In PASMCs derived from patients with PAH, HIF‐1a expression is decreased, and MLCK activity, MLC phosphorylation, and cell contraction are increased. We conclude that compromised PASMC HIF‐1a expression may contribute to the increased tone that characterizes pulmonary hypertension.—Barnes, E. A., Chen, C.‐H., Sedan, O., Cornfield, D. N. Loss of smooth muscle cell hypoxia inducible factor‐1a underlies increased vascular contractility in pulmonary hypertension. FASEB J. 31, 650–662(2017). www.fasebj.org