Heme oxygenase-1 inducer hemin prevents vascular thrombosis

Abstract

Hemin is a heme oxygenase-1 (HO-1) inducer which provides endogenous carbon monoxide known for playing roles in cell proliferation, inflammation or aggregation process. The objective of the current study was to examine the effect of prophylactic treatment with hemin in a thrombosis vascular model. Three groups of Wistar rats, control (n = 6), hemin (n = 6) and hemin + HO-1 inhibitor (n = 6), were used for this study. Hemin-treated animals received hemin (50 mg/kg/d; I.P.) for seven days and HO-1 inhibitor group received hemin at the same dose and SnPP IX (60 mg/kg/d; I.P.). All animals were exposed to electric stimulation of the left carotid according to Kawasaki's procedure to induce reproducible thrombus formation. The hemin treatment did not induce blood pressure disturbance. Effects of hemin on vascular thrombosis were quantified by histopathology and its influence on haemostasis was assessed by measuring prothrombin time (PT), activated partial thromboplastin time (APTT) and blood parameters at the end of treatment. The HO-1 mRNA and protein level variation were also checked out. Results showed that chronic treatment with hemin significantly (p < 0.01) reduced the vascular occlusion degree when compared to control and hemin SnPP groups with 7.2 +/- 4.6 vs. 71.1 +/- 14.7 and 74.0 +/- 8.8%, respectively. Moreover, we observed significant (p < 0.05) perturbations of blood parameters in hemin-treated and hemin-SnPP treated rats. Interestingly, hemin treatment did not significantly increase both PT and APTT. Finally, the HO-1 mRNA and protein levels were increased in hemin-treated carotid artery. In conclusion, hemin by inducing HO-1 expression may be a preventive agent against clinical disorders associated to an increased risk of thrombosis events and may limit haemorrhagic risks.

Carbon monoxide: Anticoagulant or procoagulant?

“…In other in vitro and in vivo investigations involving either mice or rats [24][25][26][27], COHb concentrations varied following CORM exposure, with little increase seen with CORMs that release CO quickly (e.g., CORM-3, tricarbonyldichloro(glycinato)ruthenium (II)), contrasted with COHb values between 8% to 17% after exposure to slow releasing CORMs (e.g., CORM-A1, sodium boranocarbonate, Na 2 [H 3 BCO 2 ]). In sum, when exposed to CO at low or high concentrations (based on COHb), platelet function and measures of intravascular thrombus formation were decreased in mice and rats [18][19][20][21][22][23].…”

“…significantly decreased vascular occlusion [19]. In a HO-1 deficient mouse model of allogeneic aortic transplantation, administration of CORMs or wild-type, HO-1 containing platelets prevented graft thrombosis [20].…”

“…While in vivo human investigation of the effect of CO is lacking, there are preclinical rodent models that demonstrate a profibrinolytic and/or antiplatelet effect in vitro and in vivo [18][19][20][21][22][23]. In hypercholesterolemic mice, upregulation with HO-1 with an adenovirus or exposure to inhaled CO (250 parts per million), decreased thrombus formation following carotid angioplasty, with a decrease in arterial tissue activity of plasminogen activator inhibitor-1, noted [18].…”

“…Humans and rabbit thrombi have a less dense matrix, composed of thick and thin fibrin polymers, whereas rodent clots have a more woven, matted structure. How these species-specific differences in ultrastructure impact on plasmatic coagulation kinetics and, ultimately, clinical hemostatic response to CO is Nielsen et al 19 19 Human and rabbit thrombus fibrin polymer formation is remarkably similar, whereas both rodent thrombi markedly differ from human and rabbit. Details of how these data are generated have been previously cited [94,95].…”

“…There is evidence that excessive CO exposure may result in decreased in vivo and in vitro hemostasis in humans and rodents [4][5][6][7][8][18][19][20][21][22][23], potentially by inhibition of platelet aggregation [9][10][11][12][13]15,16,[20][21][22][23]. However, there is also evidence that increased CO exposure can enhance platelet activation [14,17] and cause enhanced coagulation/decreased fibrinolysis in humans and other mammalian species [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][67][68][69][70]…”