Hypoxia-Induced Glucose-6-Phosphate Dehydrogenase Overexpression and -Activation in Pulmonary Artery Smooth Muscle Cells: Implication in Pulmonary Hypertension

Authors

Sukrutha Chettimada, Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama;
Rakhee Gupte, Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama;
Dhwajbahadur Rawat, Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama;
Sarah A. Gebb, Department of Cell Biology and Neurosciences, College of Medicine, University of South Alabama, Mobile, Alabama;
Ivan F. McMurtry, Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, Alabama; Department of Medicine, College of Medicine, University of South Alabama, Mobile, Alabama; and Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama.
Sachin A. Gupte, Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama; Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama s_gupte@nymc.edu.

Author Type(s)

Faculty

DOI

10.1152/ajplung.00229.2014

Journal Title

American Journal of Physiology. Lung Cellular and Molecular Physiology

First Page

L287

Last Page

300

Document Type

Article

Publication Date

2-1-2015

Abstract

Severe pulmonary hypertension is a debilitating disease with an alarmingly low 5-yr life expectancy. Hypoxia, one of the causes of pulmonary hypertension, elicits constriction and remodeling of the pulmonary arteries. We now know that pulmonary arterial remodeling is a consequence of hyperplasia and hypertrophy of pulmonary artery smooth muscle (PASM), endothelial, myofibroblast, and stem cells. However, our knowledge about the mechanisms that cause these cells to proliferate and hypertrophy in response to hypoxic stimuli is still incomplete, and, hence, the treatment for severe pulmonary arterial hypertension is inadequate. Here we demonstrate that the activity and expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, are increased in hypoxic PASM cells and in lungs of chronic hypoxic rats. G6PD overexpression and -activation is stimulated by H2O2. Increased G6PD activity contributes to PASM cell proliferation by increasing Sp1 and hypoxia-inducible factor 1α (HIF-1α), which directs the cells to synthesize less contractile (myocardin and SM22α) and more proliferative (cyclin A and phospho-histone H3) proteins. G6PD inhibition with dehydroepiandrosterone increased myocardin expression in remodeled pulmonary arteries of moderate and severe pulmonary hypertensive rats. These observations suggest that altered glucose metabolism and G6PD overactivation play a key role in switching the PASM cells from the contractile to synthetic phenotype by increasing Sp1 and HIF-1α, which suppresses myocardin, a key cofactor that maintains smooth muscle cell in contractile state, and increasing hypoxia-induced PASM cell growth, and hence contribute to pulmonary arterial remodeling and pathogenesis of pulmonary hypertension.

Recommended Citation

Chettimada, S., Gupte, R., Rawat, D., Gebb, S. A., McMurtry, I. F., & Gupte, S. A. (2015). Hypoxia-Induced Glucose-6-Phosphate Dehydrogenase Overexpression and -Activation in Pulmonary Artery Smooth Muscle Cells: Implication in Pulmonary Hypertension. American Journal of Physiology. Lung Cellular and Molecular Physiology, 308 (3), L287-300. https://doi.org/10.1152/ajplung.00229.2014