title: Induction of heme oxygenase-1 expression inhibits platelet-dependent thrombosis.
abstract: Heme oxygenase-1 (HO-1) plays a key role in protecting tissue from oxidative stress. Although some studies implicate HO-1 in modulating thrombosis after vascular injury, the impact of HO-1 on the rate of clot formation in vivo is poorly defined. This study examined the potential function of HO-1 in regulating platelet-dependent arterial thrombosis. Platelet-rich thrombi were induced in C57BL/6J mice by applying 10% ferric chloride to the exposed carotid artery. Mean occlusion time of wild-type mice (n = 10) was 14.6 +/- 1.0 min versus 12.9 +/- 0.6 min for HO-1-/- mice (n = 11, p = 0.17). However, after challenge with hemin, mean occlusion time was significantly longer in wild-type mice (16.3 +/- 1.2 min, n = 15) than HO-1-/- mice (12.0 +/- 1.0 min, n = 9; p = 0.021). Hemin administration induced an approximately twofold increase in oxidative stress, measured as plasma thiobarbituric acid reactive substances. Immunohistochemical analysis revealed that hemin induced a robust increase in HO-1 expression within the carotid arterial wall. Ex vivo blood clotting within a collagen-coated perfusion chamber was studied to determine whether the accelerated thrombosis observed in HO-1-/- mice was contributed to by effects on the blood itself. Under basal conditions, mean clot formation during perfusion of blood over collagen did not differ between wild-type mice and HO-1-/- mice. However, after hemin challenge, mean clot formation was significantly increased in HO-1-/- mice compared with wild-type controls. These results suggest that, under basal conditions, HO-1 does not exert a significant effect on platelet-dependent clot formation in vivo. However, under conditions that stimulate HO-1 production, platelet-dependent thrombus formation is inhibited by HO-1. Enhanced HO-1 expression in response to oxidative stress may represent an adaptive response mechanism to down-regulate platelet activation under prothrombotic conditions.
authors.forename: Lin
authors.initials: L
authors.lastname: Peng
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Mundada
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Stomel
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Liu
authors.forename: Jinhong
authors.initials: J
authors.lastname: Sun
authors.forename: Shaw-Fang
authors.initials: SF
authors.lastname: Yet
authors.forename: William P
authors.initials: WP
authors.lastname: Fay
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004790:Enzyme Induction; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013927:Thrombosis
chemical_list: D008565:Membrane Proteins; D017392:Thiobarbituric Acid Reactive Substances; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse