title: Heme-oxygenase induction inhibits arteriolar thrombosis in vivo: effect of the non-substrate inducer cobalt protoporphyrin.
abstract: Heme oxygenase-1 (HO) metabolizes heme to form the vasodilator carbon monoxide and antioxidant biliverdin. Upregulation of HO-1 by hemin, which is also a substrate attenuates thrombosis in rodent models, however, whether protection is due to HO-1 upregulation or to increased substrate availability is unknown. This study tested the hypothesis that treatment of mice with cobalt protoporphyrin (CoPP), a non-substrate HO-1 inducer, would protect the endothelium from laser injury. C57Bl/J6 mice were treated with vehicle, CoPP (20 mg/kg), CoPP plus the HO-1 inhibitor tin protoporphyrin (SnPP; 20 mg/kg) or SnPP alone for 18 h. Intravital microscopy was used to quantitate thrombus formation in cremaster arterioles in response to laser ablation of the endothelium. CoPP treatment inhibited thrombosis by 43% compared to vehicle (P<0.05). SnPP co-treatment negated the inhibitory effect of CoPP while SnPP alone potentiated thrombosis compared to vehicle. In CoPP-treated animals, cremaster HO-1 mRNA expression was increased 59+/-17-fold over vehicle (P<0.001). Co-treatment with CoPP+SnPP attenuated this effect by 36%, however the increase in HO-1 protein induced by CoPP was unaffected by SnPP. Induction of HO-1 by the non-substrate inducer CoPP protects against laser induced endothelial injury without the need for increased substrate. Small molecule, substrate-independent upregulation of HO-1 expression represents a feasible approach to ameliorate endothelial dysfunction in cardiovascular disease.
authors.affiliation: Department of Cardiovascular Pharmacology, Metabolic Pathways Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406, United States. Douglas_Johns@merck.com
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Johns
authors.forename: Dorothy
authors.initials: D
authors.lastname: Zelent
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Ao
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Bradley
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cooke
authors.forename: Lisa
authors.initials: L
authors.lastname: Contino
authors.forename: Erding
authors.initials: E
authors.lastname: Hu
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Douglas
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jaye
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007834:Lasers / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology*; D013927:Thrombosis / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1