Heme oxygenase-1 induction modulates hypoxic pulmonary vasoconstriction through upregulation of ecSOD.
Endothelium-denuded bovine pulmonary arteries (BPA) contract to hypoxia through a mechanism potentially involving removing a superoxide-derived hydrogen peroxide-mediated relaxation. BPA organ cultured for 24 h with 0.1 mM cobalt chloride (CoCl(2)) to increase the expression and activity of heme oxygenase-1 (HO-1) is accompanied by a decrease in 5 microM lucigenin-detectable superoxide and an increase in horseradish peroxidase-luminol detectable peroxide levels. Force development to KCl in BPA was not affected by increases in HO-1, but the hypoxic pulmonary vasoconstriction (HPV) response was decreased. Organ culture with a HO-1 inhibitor (10 microM chromium mesoporphyrin) reversed the effects of HO-1 on HPV and peroxide. Treatment of HO-1-induced BPA with extracellular catalase resulted in reversal of the attenuation of HPV without affecting the force development to KCl. Increasing intracellular peroxide scavenging with 0.1 mM ebselen increased force development to KCl and partially reversed the decrease in HPV seen on induction of HO-1. HO-1 induction increases extracellular (ec) superoxide dismutase (SOD) expression without changing Cu,Zn-SOD and Mn-SOD levels. HO-1-induced BPA rings treated with the copper chelator 10 mM diethyldithiocarbamate to inactivate ecSOD and Cu,Zn-SOD showed increased superoxide and decreased peroxide to levels equal to non-HO-1-induced rings, whereas the addition of SOD to freshly isolated BPA rings attenuated HPV similar to HO-1 induction with CoCl(2). Therefore, HO-1 induction in BPA increases ecSOD expression associated with enhanced generation of peroxide in amounts that may not be adequately removed during hypoxia, leading to an attenuation of HPV.
Ahmad
Mansoor
M
Departments of Physiology, New York Medical College, Valhalla, New York 10595, USA.
Zhao
Xiangmin
X
Kelly
Melissa R
MR
Kandhi
Sharath
S
Perez
Oscar
O
Abraham
Nader G
NG
Wolin
Michael S
MS
D000818:Animals; D001393:Azoles / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D002417:Cattle; D015687:Cell Hypoxia; D002614:Chelating Agents / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D004050:Ditiocarb / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D054833:Isoindoles; D008652:Mesoporphyrins / Q000494:pharmacology; D009924:Organ Culture Techniques; D016566:Organoselenium Compounds / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology*; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D001393:Azoles; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D054833:Isoindoles; D008652:Mesoporphyrins; D016566:Organoselenium Compounds; D014662:Vasoconstrictor Agents; C427471:chromium mesoporphyrin; D013481:Superoxides; D003035:Cobalt; C042986:ebselen; D011189:Potassium Chloride; D003300:Copper; D004050:Ditiocarb; D006861:Hydrogen Peroxide; D002374:Catalase; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; C018021:cobaltous chloride