Abstract-Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. Our previous studies demonstrated an important interaction between nuclear factor-B (NF-B) activation and homocysteine (
Objective-The stimulatory effect of homocysteine (Hcy) on monocyte chemoattractant protein (MCP)-1 expression in vitro has been suggested to play an important role in Hcy-mediated atherosclerosis. We investigated whether such a stimulatory effect occurs in vivo, leading to monocyte adhesion to the endothelium. Methods and Results-Sprague-Dawley rats were divided into 4 groups. Hyperhomocysteinemia was induced in 1 group of rats after 4 weeks of a high-methionine diet (serum Hcy levels were 4-to 5-fold higher than levels in control rats).The number of ED-1-positive cells present on the surface of aortic endothelium was significantly elevated in hyperhomocysteinemic rats. There was a significant increase in the expression of MCP-1, vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in the endothelium. Antibodies recognizing MCP-1, VCAM-1, or E-selectin could abolish the enhanced monocyte binding to the aortic endothelium of hyperhomocysteinemic rats. Endotheliumdependent aortic relaxation was impaired in hyperhomocysteinemic rats. Conclusions-These results suggest that in the absence of other known risk factors, hyperhomocysteinemia stimulates the expression of MCP-1, VCAM-1, and E-selectin in vivo, leading to increased monocyte adhesion to the aortic endothelium. Such an effect may contribute significantly to the development of atherosclerosis by facilitating monocyte/macrophage infiltration into the arterial wall. Key Words: hyperhomocysteinemia Ⅲ atherosclerosis Ⅲ monocyte chemoattractant protein-1 Ⅲ cytokines Ⅲ monocytes H yperhomocysteinemia is now regarded as one of the important risk factors for cardiovascular and cerebral vascular disorders. 1 Elevated homocysteine (Hcy) levels in the blood have been observed in a significant proportion of patients with coronary artery disease. 2 Several plausible mechanisms for Hcy-induced atherosclerosis have been proposed. These include endothelial dysfunction, 3 increased proliferation of smooth muscle cells, 4 enhanced coagulability, 5 and increased cholesterol synthesis in hepatocytes. 6 Endothelial dysfunction is considered to be one of the important mechanisms contributing to atherogenesis. It has been proposed that Hcy-caused endothelial injury may be due to oxidative stress, attenuation of NO-mediated vasodilatation, and disturbance in the antithrombotic activities of the endothelium. 7 On injury, endothelial cells are capable of producing various cytokines and growth factors that participate in inflammatory reactions in the arterial wall.Dysfunction of endothelial cells is the key process promoting inflammatory reactions. One of the earliest detectable cellular responses in the formation of atherosclerotic lesions is the local recruitment of monocytes by the vascular endothelium. 8 Such localized accumulation of monocytes is mediated by endothelial expression of specific adhesion/chemoattractant molecules. 8,9 Monocyte chemoattractant protein (MCP)-1 is a potent chemokine that stimulates the migration of monocytes into the intima of the arterial wall. 8 ...
The present study clearly demonstrates that enhanced MCP-1 expression in rat kidney during ischemia/reperfusion injury is mediated by NF-kappaB activation and oxidative stress. Elevated MCP-1 expression might be responsible for increased monocyte infiltration in the injured kidney.
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