Heme Oxygenase-1 Deficiency Accelerates Formation of Arterial Thrombosis Through Oxidative Damage to the Endothelium, Which Is Rescued by Inhaled Carbon Monoxide

Abstract

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.

Induction of Heme Oxygenase-1 is a Beneficial Response in a Murine Model of Venous Thrombosis

“…37 In studies in which arterial thrombosis was induced by the application of photochemical stress to the carotid artery, such arterial thrombosis occurred more rapidly in HO-1 Ϫ/Ϫ mice. 38 In these latter studies, HO-1 Ϫ/Ϫ mice did not exhibit any intrinsic defects in hemostasis as assessed either by bleeding time, prothrombin time, or platelet counts. These findings, in conjunction with unaltered clot formation either in vivo or ex vivo in HO-1 Ϫ/Ϫ mice subjected to the ferric chloride model, indicate that there are no intrinsic defects in hemostatic function in the unstressed state in HO-1 Ϫ/Ϫ mice.…”

“…37,38 In studies in which arterial thrombosis was induced by the application of ferric chloride to the carotid artery, the occlusion time for arterial thrombosis was not different in HO-1 ϩ/ϩ and HO-1 Ϫ/Ϫ mice nor was ex vivo blood clotting in collagen-coated capillary tubes altered in HO-1 Ϫ/Ϫ mice as compared to HO-1 ϩ/ϩ mice. 37 However, under conditions of oxidative stress as induced by hemin, arterial clot formation was hastened in HO-1 Ϫ/Ϫ mice.…”

Increased levels of plasma haemoxygenase-1 in prostate cancer

“…However, possible roles in different pathophysiology patterns are emerging, such as protection of the endothelium from oxidative stress. 4,6,7 HO-1 may also be important in cardiovascular disease and in apoptosis, 5,9,19,20 and there is also evidence that HO-1 may be linked experimentally to angiogenesis via VEGF. [10][11][12]18,21 It is therefore notable that we report good correlations between HO-1 and VEGF (r40.52) (although we acknowledge the possibility of small number error) in the absence of cancer, but that this correlation in markedly weaker in the presence of cancer (r ¼ 0.12).…”

“…3 Deficiency of this enzyme leads to severe multi-system disease including vascular damage, as is supported by increased plasma von Willebrand factor (vWf), 4 and it has also been implicated in other models of vascular pathology. [5][6][7] Other reports suggest roles for HO-1 in defence from viraemia, from oxidant stress, in inflammation and in cardiovascular disease. 8,9 Notably, there are several reports linking HO-1 with cancer, possibly via interactions with VEGF, 10,11 suggesting a role in angiogenesis.…”

Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential

“…Independently, major pathological alterations of the endothelium have been observed in HO-1 knockout mice, in which endothelial cells were more susceptible to apoptotic cell death and denudation from the extracellular matrix [31]. Independently, anti-inflammatory endothelial protection via HO-1 has been shown to be mediated via its ability to down-regulate TNF-induced expression of various adhesion molecules [32,33].…”