title: Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide.
abstract: This study examines in endothelium-denuded bovine pulmonary arteries the effects of increasing heme oxygenase-1 (HO-1) activity on relaxation and soluble guanylate cyclase (sGC) activation by nitric oxide (NO). A 24-h organ culture with 0.1 mM cobalt chloride (CoCl2) or 30 microM Co-protoporphyrin IX was developed as a method of increasing HO-1 expression. These treatments increased HO-1 expression and HO activity by approximately two- to fourfold and lowered heme levels by 40-45%. Induction of HO-1 was associated with an attenuation of pulmonary arterial relaxation to the NO-donor spermine-NONOate. The presence of a HO-1 inhibitor 30 microM chromium mesoporphyrin during the 24-h organ culture (but not acute treatment with this agent) reversed the attenuation of relaxation to NO seen in arteries co-cultured with agents that increased HO-1. Relaxation to isoproterenol, which is thought to be mediated through cAMP, was not altered in arteries with increased HO-1. Inducers of HO-1 did not appear to alter basal sGC activity in arterial homogenates or expression of the beta(1)-subunit of sGC. However, the increase in activity seen in the presence of 1 microM spermine-NONOate was attenuated in homogenates obtained from arteries with increased HO-1. Since arteries with increased HO-1 had decreased levels of superoxide detected by the chemiluminescence of 5 microM lucigenin, superoxide did not appear to be mediating the attenuation of relaxation to NO. These data suggest that increasing HO-1 activity depletes heme, and this is associated with an attenuation of pulmonary artery relaxation and sGC activation responses to NO.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mingone
authors.forename: Mansoor
authors.initials: M
authors.lastname: Ahmad
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Gupte
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Chow
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
mesh_terms: D000166:Acridines / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D003035:Cobalt / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D006418:Heme / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007545:Isoproterenol / Q000494:pharmacology; D049449:Luminescence; D008652:Mesoporphyrins / Q000494:pharmacology; D009119:Muscle Contraction / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011524:Protoporphyrins / Q000494:pharmacology; D011651:Pulmonary Artery / Q000378:metabolism / Q000502:physiology*; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
chemical_list: D000166:Acridines; D000318:Adrenergic beta-Agonists; D008652:Mesoporphyrins; D011524:Protoporphyrins; C427471:chromium mesoporphyrin; D013481:Superoxides; C091861:spermine nitric oxide complex; C033472:10,10'-dimethyl-9,9'-biacridinium; D013096:Spermine; D009569:Nitric Oxide; D003035:Cobalt; D006418:Heme; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; D006162:Guanylate Cyclase; C018021:cobaltous chloride; D007545:Isoproterenol