title: Dehydroepiandrosterone promotes pulmonary artery relaxation by NADPH oxidation-elicited subunit dimerization of protein kinase G 1α.
abstract: The activity of glucose-6-phosphate dehydrogenase (G6PD) controls a vascular smooth muscle relaxing mechanism promoted by the oxidation of cytosolic NADPH, which has been associated with activation of the 1α form of protein kinase G (PKG-1α) by a thiol oxidation-elicited subunit dimerization. This PKG-1α-activation mechanism appears to contribute to responses of isolated endothelium-removed bovine pulmonary arteries (BPA) elicited by peroxide, cytosolic NADPH oxidation resulting from G6PD inhibition, and hypoxia. Dehydroepiandrosterone (DHEA) is a steroid hormone with pulmonary vasodilator activity, which has beneficial effects in treating pulmonary hypertension. Because multiple mechanisms have been suggested for the vascular effects of DHEA and one of the known actions of DHEA is inhibiting G6PD, we investigated whether it promoted relaxation associated with NADPH oxidation, PKG-1α dimerization, and PKG activation detected by increased vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Relaxation of BPA to DHEA under aerobic or hypoxic conditions was associated with NADPH oxidation, PKG-1α dimerization, and increased VASP phosphorylation. The vasodilator activity of DHEA was markedly attenuated in pulmonary arteries and aorta from a PKG knockin mouse containing a serine in place of a cysteine involved in PKG dimerization. DHEA promoted increased PKG dimerization in lungs from wild-type mice, which was not detected in the PKG knockin mouse model. Thus PKG-1α dimerization is a major contributing factor to the vasodilator actions of DHEA and perhaps its beneficial effects in treating pulmonary hypertension.
authors.affiliation: Dept. of Physiology, New York Medical College, Valhalla, NY 10595. mike_wolin@nymc.edu).
authors.forename: Dhara
authors.initials: D
authors.lastname: Patel
authors.forename: Sharath
authors.initials: S
authors.lastname: Kandhi
authors.forename: Melissa
authors.initials: M
authors.lastname: Kelly
authors.forename: Boon Hwa
authors.initials: BH
authors.lastname: Neo
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000378:metabolism; D015687:Cell Hypoxia; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009249:NADP / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D021122:Protein Subunits; D014665:Vasodilator Agents; D000098662:Vasodilator-Stimulated Phosphoprotein; C091861:spermine nitric oxide complex; D013096:Spermine; D003687:Dehydroepiandrosterone; D009249:NADP; D006861:Hydrogen Peroxide; D005954:Glucosephosphate Dehydrogenase; D019255:NADPH Oxidases; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D000109:Acetylcholine
keywords: cGMP; glucose-6-phosphate dehydrogenase; pulmonary hypertension