Study On The Mechanism Of Vascular Endothelial Injury Induced By Smoke Exposure And Drug Protection

Part I Protective effect of melatonin on cigarette smoke-induced restenosis in rat carotid arteries after balloon injuryCigarette smoking, the single most significant source of toxic chemical exposure to humans, is one of the most important causes of atherosclerotic vascular diseases. Vascular restenosis after the interventional angioplasty remains the main obstacle to a favorable long-term patency. Many researches suggest that cigarette smoking is one of the most important causes of restenosis and the inflammatory reaction induced by smoking may contribute to the high incidence of restenosis. The current study was designed to investigate whether melatonin could protect against the cigarette smoke-induced restenosis in rat carotid arteries after balloon injury. Three groups of male rats (normal condition, cigarette smoke exposed, cigarette smoke exposed and melatonin injected) were used in this study. An established balloon-induced carotid artery injury was performed and the carotid arteries were harvested from these three groups fourteen days later. The ratio of intima to media, the infiltration of inflammatory cells, the expression of inflammatory cytokines (NF-κB, IL-1β, IL-6, TNF-α, MCP-1), adhesion molecules (ICAM-1, VCAM-1) and eNOS were measured. The results showed that cigarette smoke exposure aggravated the stenosis of the lumen, promoted the infiltration of inflammatory cells and induced the expression of the inflammatory cytokines and adhesion molecules after the balloon-induced carotid artery injury. Moreover, cigarette smoke exposure can inhibit the expression of eNOS. Particularly, we surperised that melatonin could minimize this effect caused by cigarette smoke. These results suggested that melatonin could prevent the cigarette smoke-induced restenosis in rat carotid arteries after balloon injury and the mechanism of its protective effect may be the inhibition of the inflammatory reaction. This also implies melatonin has the potential therapeutic applicability in prevention of restenosis after the vascular angioplasty in smokers.Part II Hemin prevents cigarette smoke-induced restenosis after vascular angioplasty in rat model by inducing heme-oxygenase-1Cigarette smoking, a major independent risk factor of atherosclerosis, can cause inflammatory injury of vascular. Many researches suggest smokers have a higher incidence of restenosis than non-smokers after the vascular angioplasty. Heme oxygenase-1 (HO-1) is an endogenous cytoprotective enzyme and can play an anti-inflammatory role in cells. This study was designed to investigate whether hemin, a potent HO-1 inducer, could protect against the cigarette smoke-induced restenosis in rat carotid arteries after balloon injury. The results showed that cigarette smoke exposure aggravated the stenosis of the lumen, promoted the infiltration of inflammatory cells and induced the expression of the inflammatory cytokines (NF-κB, IL-1β,IL-6, TNF-a, MCP-1) and adhesion molecules (ICAM-1, VCAM-1) after the balloon-induced carotid artery injury. Particularly, we found that hemin could minimize this effect caused by cigarette smoke. Furthermore, the beneficial effects of hemin were abolished in the presence of Zincprotoporphyrin IX (ZnPP), a HO-1 inhibitor. These results suggested that hemin could prevent the cigarette smoke-induced restenosis in rat carotid arteries after balloon injury and the mechanism of its protective effect may be the inhibition of the inflammatory reaction. This also implies hemin has the potential therapeutic applicability in prevention of restenosis after the vascular angioplasty in smokers.Part Ⅲ Antioxidant effect of heme oxygenase-1 on cigarette smoke-induced vascular injuryCigarette smoking, the leading cause of preventable morbidity and mortality in the world, can cause oxidative and inflammatory damage of vascular. Heme oxygenase-1 (HO-1) is an endogenous cytoprotective enzyme and can play an antioxidant role in cells. The aim of this study was to investigate whether HO-1 could protect vascular and endothelial cells from the oxidative damage induced by cigarette smoking. We observed that cigarette smoking could induce the generation of the reactive oxygen species (ROS) in carotid arteries of rats. Hemin, a widely used HO-1 inducer, could reduce the generation of ROS. Also, the serum of smoking rats could cause the increasing of ROS in human umbilical vein endothelial cells (HUVECs) and the protective effect of hemin was observed too. Taken together, the present study demonstrates that cigarette smoking can cause the oxidative damage of the vascular and HUVECs by inducing the generation of ROS and HO-1 can play an antioxidant effect in the course. This also implies hemin may have potential therapeutic applicability in prevention of vascular diseases caused by cigarette smoking.