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Activation of Glucose‐6‐Phosphate Dehydrogenase Promotes Acute Hypoxic Pulmonary Artery Contraction
Author(s) -
Rawat Dhawjbahadur K,
Gupte Rakhee S,
Chettimada Sukrutha,
McMurtry Ivan F,
Gupte Sachin A
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.795.6
Subject(s) - hypoxia (environmental) , nad+ kinase , reactive oxygen species , glycolysis , chemistry , myosin light chain kinase , hypoxic pulmonary vasoconstriction , dehydrogenase , lactate dehydrogenase , warburg effect , glucose 6 phosphate dehydrogenase , pyruvate dehydrogenase kinase , mitochondrial ros , phosphorylation , medicine , enzyme , biochemistry , oxygen , endocrinology , vasoconstriction , pyruvate dehydrogenase complex , biology , organic chemistry
Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to a decrease in airway O 2 tension, but the underlying mechanism is incompletely understood. We studied the contribution of glucose‐6‐phosphate dehydrogenase (G6PD), an important regulator of NADPH redox and production of reactive oxygen species, to the development of HPV. We found that hypoxia (95%N2‐5%CO2) increased contraction of bovine pulmonary artery (PA) precontracted with KCl or serotonin. Depletion of extracellular glucose reduced NADPH, NADH and HPV, substantiating the idea that glucose metabolism and G6PD play roles in the response of PA to hypoxia. Our data also show that inhibition of glycolysis and mitochondrial respiration (indicated by an increase in NAD + and decrease in the ATP‐to‐ADP ratio) by hypoxia, or by inhibitors of pyruvate dehydrogenase or electron transport chain complexes I or III, increased generation of reactive oxygen species, which in turn activated G6PD. Silencing G6PD expression in PA using a targeted siRNA abolished HPV and diminished Ca 2+ ‐independent and Ca 2+ ‐dependent myosin light chain phosphorylation otherwise increased by hypoxia. Similarly, G6PD expression and activity were significantly reduced in lungs from G6PD mut(−/−) mice, and there was a corresponding reduction in HPV. Finally, regression analysis relating G6PD activity and the NADPH‐to‐NADP+ ratio to the HPV response clearly indicated a positive linear relationship between G6PD activity and HPV. Based on these findings, we propose that G6PD and NADPH redox are crucially involved in the mechanism of HPV and, in turn, may play a key role in increasing pulmonary arterial pressure, which is involved in the development of pulmonary hypertension. (Supported by NIH grant RO1HL085352)