Activation of glucose-6-phosphate dehydrogenase promotes acute hypoxic pulmonary artery contraction.

Abstract

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 (Glc-6-PD), an important regulator of NADPH redox and production of reactive oxygen species, to the development of HPV. We found that hypoxia (95% N(2), 5% CO(2)) 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 Glc-6-PD 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 Glc-6-PD. Inhibition of Glc-6-PD decreased Ca(2+) sensitivity to the myofilaments and diminished Ca(2+)-independent and -dependent myosin light chain phosphorylation otherwise increased by hypoxia. Silencing Glc-6-PD expression in PA using a targeted small interfering RNA abolished HPV and decreased extracellular Ca(2+)-dependent PA contraction increased by hypoxia. Similarly, Glc-6-PD expression and activity were significantly reduced in lungs from Glc-6-PD(mut(-/-)) mice, and there was a corresponding reduction in HPV. Finally, regression analysis relating Glc-6-PD activity and the NADPH-to-NADP(+) ratio to the HPV response clearly indicated a positive linear relationship between Glc-6-PD activity and HPV. Based on these findings, we propose that Glc-6-PD 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.

• Authors: Rakhee S Gupte, Dhawjbahadur K Rawat, Sukrutha Chettimada, Donna L Cioffi, Michael S Wolin, William T Gerthoffer, Ivan F McMurtry, Sachin A Gupte
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 25 Pg. 19561-71 (Jun 18 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20363753 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• NADP
• Glucosephosphate Dehydrogenase
• Glucose
• Calcium

Topics

• Animals
• Blood Pressure
• Calcium (metabolism)
• Cattle
• Enzyme Activation
• Glucose (metabolism)
• Glucosephosphate Dehydrogenase (metabolism)
• Hypoxia
• Lung (pathology)
• NADP (metabolism)
• Oxidation-Reduction
• Phosphorylation
• Pulmonary Artery (enzymology)
• Vasoconstriction