title: Cytosolic NADH redox and thiol oxidation regulate pulmonary arterial force through ERK MAP kinase.
abstract: An ERK MAP kinase-mediated contractile mechanism previously reported to be activated by peroxide and stretch in bovine coronary arteries is shown in this study to be present in endothelium-denuded bovine pulmonary arteries and subject to regulation by modulation of cytosolic NAD(H) redox through the lactate dehydrogenase reaction. Although our previous work identified an acute PO2-dependent peroxide-mediated relaxation of bovine pulmonary arteries on exposure to lactate, a 30-min treatment with 10 mM lactate enhanced ERK phosphorylation and increased force generation to 30 mM KCl. Hypoxia inhibited these responses to lactate. Increases in ERK phosphorylation and the enhancement of force generation by lactate and stretch are attenuated in the presence of inhibitors of Nox oxidase (0.1 mM apocynin) or ERK activation (10 microM PD-98059) and by 0.1 mM ebselen. Additionally, incubation of pulmonary arteries with 10 mM pyruvate lowered basal levels of ERK phosphorylation, and it inhibited both the ERK phosphorylation and the enhancement in force generation to 30 mM KCl caused by stretch. Treatment of pulmonary arteries with the thiol oxidant diamide (1 microM) elicited what appears to be a peroxide-independent increase in force and ERK phosphorylation that were both attenuated by PD-98059. Thus pulmonary arteries possess a peroxide-elicited contractile mechanism involving ERK MAP kinase, which is stimulated by stretch and regulated through the control of Nox oxidase activity by the availability of cytosolic NADH.
authors.affiliation: Dept. of Physiology, Basic Science Bldg., Rm. 604, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Oeckler
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Arcuino
authors.forename: Mansoor
authors.initials: M
authors.lastname: Ahmad
authors.forename: Susan C
authors.initials: SC
authors.lastname: Olson
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
mesh_terms: D000818:Animals; D002417:Cattle; D015687:Cell Hypoxia; D003600:Cytosol / Q000378:metabolism*; D003958:Diamide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology*; D019289:Pyruvic Acid / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D016877:Oxidants; D013438:Sulfhydryl Compounds; D009243:NAD; D003958:Diamide; D019344:Lactic Acid; D019289:Pyruvic Acid; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases