Carbon monoxide-induced early thrombolysis contributes to heme oxygenase-1-mediated inhibition of neointimal growth after vascular injury in hypercholesterolemic mice.
Arterial thrombosis is a critical event in the pathogenesis of lesion development. In this study, we evaluated the effect of heme oxygenase-1 (HO-1), a stress-inducible enzyme with vasoprotective functions, on arterial thrombosis following vascular mechanical injury. The carotid arteries of apoE-deficient mice were subjected to angioplasty with a modified beaded-needle. Arterial thrombosis occurred at 12 h after injury. Treatment of the injured vessels with an adenovirus bearing HO-1 gene (Adv-HO-1) (1 x 10(8) pfu), but not saline or empty adenovirus (Adv), immediately after angioplasty resulted in earlier thrombolysis and restoration of blood flow detected at 24 h. Immunohistochemistry revealed that the arterial plasminogen activator inhibitor-1 (PAI-1) expression was markedly reduced in Adv-HO-1-treated injured arteries as compared to control counterparts. The thrombolytic effect was also observed by exposing animals with existing arterial thrombosis to carbon monoxide (CO) (250 ppm, 2 h), a byproduct derived from heme degradation by HO-1. In parallel with less fibrin(ogen) deposition, the macrophage infiltration, monocyte chemoattractant protein-1 expression and neointimal formation assessed at 2 weeks after angioplasty were substantially reduced in injured arteries treated with Adv-HO-1. These results support a role of early thrombolysis induced by CO in HO-1-mediated protection against intimal hyperplasia after vascular injury.
Chen
Yen-Hui
YH
Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan, Republic of China.
Tsai
Hui-Ling
HL
Chiang
Ming-Tsai
MT
Chau
Lee-Young
LY
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D002248:Carbon Monoxide / Q000502:physiology*; D017536:Carotid Artery, Common / Q000503:physiopathology*; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000502:physiology*; D006937:Hypercholesterolemia / Q000503:physiopathology*; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D024510:Muscle Development; D009131:Muscle, Smooth, Vascular / Q000254:growth & development; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D013927:Thrombosis / Q000503:physiopathology*; D014161:Transduction, Genetic
D001057:Apolipoproteins E; D017395:Plasminogen Activator Inhibitor 1; D002248:Carbon Monoxide; D005337:Fibrin; D005340:Fibrinogen; D051547:Heme Oxygenase-1