Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium, which is rescued by inhaled carbon monoxide

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Abstract

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 reactive oxygen species 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 reactive oxygen species during vascular damage. Induction of HO-1 may be beneficial in the prevention of thrombosis associated with vascular oxidant stress and inflammation. © 2007 American Heart Association, Inc.

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APA

True, A. L., Olive, M., Boehm, M., San, H., Westrick, R. J., Raghavachari, N., … Nabel, E. G. (2007). Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium, which is rescued by inhaled carbon monoxide. Circulation Research, 101(9), 893–901. https://doi.org/10.1161/CIRCRESAHA.107.158998

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