Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium, which is rescued by inhaled carbon monoxide.
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.
True
Andrea L
AL
National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
Olive
Michelle
M
Boehm
Manfred
M
San
Hong
H
Westrick
Randal J
RJ
Raghavachari
Nalini
N
Xu
Xiuli
X
Lynn
Edward G
EG
Sack
Michael N
MN
Munson
Peter J
PJ
Gladwin
Mark T
MT
Nabel
Elizabeth G
EG
D000280:Administration, Inhalation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001664:Biliverdine / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006412:Hematopoietic Stem Cells / Q000201:enzymology; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics*; D006487:Hemostasis / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000502:physiology; D010641:Phenotype; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D014841:von Willebrand Factor / Q000378:metabolism
D014841:von Willebrand Factor; D002248:Carbon Monoxide; D013925:Thromboplastin; D051547:Heme Oxygenase-1; D001664:Biliverdine