Published online before print September 20, 2007, doi: 10.1161/CIRCRESAHA.107.158998
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Submitted on September 20, 2005
Accepted on September 12, 2007
Heme Oxygenase-1 Deficiency Accelerates Formation of Arterial Thrombosis Through Oxidative Damage to the Endothelium, Which Is Rescued by Inhaled Carbon Monoxide
Andrea L. True ;
From the National Heart, Lung and Blood Institute (A.L.T., M.O., M.B., H.S., N.R., X.X., E.G.L., M.N.S., M.T.G., E.G.N.), and Center for Information Technology (P.J.M.), NIH, Bethesda, Md; and University of Michigan Medical Center (R.J.W.), Ann Arbor.
* To whom correspondence should be addressed. E-mail: nabele{at}nhlbi.nih.gov.
Heme oxygenase (HO)-1 (encoded by Hmox1) catalyzes the oxidative degradation of heme to biliverdin and carbon monoxide. HO-1 is induced during inflammation and oxidative stress to protect tissues from oxidative damage. Because intravascular thrombosis forms at sites of tissue inflammation, we hypothesized that HO-1 protects against arterial thrombosis during oxidant stress. To investigate the direct function of HO-1 on thrombosis, we used photochemical-induced vascular injury in Hmox1-/- and Hmox1+/+ mice. Hmox1-/- mice developed accelerated, occlusive arterial thrombus compared with Hmox1+/+ mice, and we detected several mechanisms accounting for this antithrombotic effect. First, endothelial cells in Hmox1-/- arteries were more susceptible to apoptosis and denudation, leading to platelet-rich microthrombi in the subendothelium. Second, tissue factor, von Willebrand Factor, and ROS were significantly elevated in Hmox1-/- mice, consistent with endothelial cell damage and loss. Third, following transplantation of Hmox1-/- donor bone marrow into Hmox1+/+ recipients and subsequent vascular injury, we observed rapid arterial thrombosis compared with Hmox1+/+ mice receiving Hmox1+/+ bone marrow. Fourth, inhaled carbon monoxide and biliverdin administration rescued the prothrombotic phenotype in Hmox1-/- mice. Fifth, using a transcriptional analysis of arterial tissue, we found that HO-1 determined a transcriptional response to injury, with specific effects on cell cycle regulation, coagulation, thrombosis, and redox homeostasis. These data provide direct genetic evidence for a protective role of HO-1 against thrombosis and ROS during vascular damage. Induction of HO-1 may be beneficial in the prevention of thrombosis associated with vascular oxidant stress and inflammation.
Key words: heme oxygenase • thrombosis • endothelium • apoptosis • vascular biology