转染细胞色素P450表氧化酶基因对TNF-α损伤大鼠内皮依赖性血管舒张反应的保护作用及机制研究  

Gene Delivery with Cytochrome P4SO Arachidonic Add Epoxygenase Prevented Endothelium-de-pendent Vasodilatation Impairment Induced by TNF-a in Rat

作　　者：王家宁[1] 萧斌[1] 汪培华[1] 杨仕林[1] 汪道文[1] 

机构地区：[1]华中科技大学同济医学院附属同济医院高血压研究所 内科,武汉市430030

出　　处：《中国分子心脏病学杂志》2006年第3期136-139,共4页Molecular Cardiology of China

基　　金：国家自然科学基金项目(No.30430320;30270561);科技部国际合作项目(No.2005DFA30880)资助

摘　　要：目的研究过度表达表氧化酶基因,增加内源性EETs的产生是否对TNF-α损伤大鼠内皮依赖性血管舒张反应具有保护作用,并初步从对血管VCAM-1表达的影响探讨其机制。方法将携带细胞色素P450表氧化酶基因的真核表达载体pCB6质粒导入大鼠体内,2周后经静脉给予TNF-α,6 h后观察去甲肾上腺素预收缩的主动脉血管环对乙酰胆碱的舒张反应,并以western blot 检测血管中VCAM-1蛋白质的表达情况。结果 TNF-α降低了主动脉环对乙酰胆碱的舒张反应, CYP2C11、CYP2J2和CYPF87V基因转染使得这种被TNF-α降低的血管舒张反应增强。TNF-α增加了血管VCAM-1表达,CYP2C11、CYP2J2和CYPF87V基因转染使得这种被TNF-α诱导的VCAM-1表达减少。结论CYP2C11、CYP2J2和CYPF87V基因能提高了血管对舒血管物质的反应性。本研究提示,通过上调体内表氧化酶基因表达水平提高内源性EETs浓度可减轻炎症介导的血管损伤,这为研究动脉粥样硬化的防治提供了新的思路。Objectives To study whether overexpression of epoxygenase gene can prevent endotheli- um-dependent vasodilatation impairment induced by TNF-α. Methods Male Sprague-Dawley rats were divided into five groups randomly and injected intravenously with a construct containing with CYP2C11, CYP2J2 or CYPF87V cDNA and empty plasmid and saline was used as control, respectively. Two weeks later, TNF-α was injected intravenously（ 10μg/Kg）. Six to eight hours after injection of TNF（, the aortic ring response to vasoactive drugs was tested using 4-channel instrument, and the expression of VCAM-1 in aortic vessel was probed using Western Blots. Results The relaxation response of aortic ring to acetylcholine was decreased by TNF-α. However, the forced overexpression of CYP2C11, CYP2J2 and CYPF87V attenuated the toxic effects in part. Western Blots showed that the expression of VCAM-1 in aortic vessel was upregulated by TNF-α. However, overexpression of CYP2C11, CYP2J2 and CYPF87V inhibited the effects. Conclusion The delivery of CYP2C11, CYP2J2 and CYPF87V Genes can improved the relaxation reaction of vessels to acetylcholine, and the mechanisms are involved in inhibiting the inflammation. These results provide a new insight into understanding endogenous protection via CYP epoxygenase and EETs and development of new strategies for the treatment of atherosclerosis.

关 键 词：花生四烯酸细胞色素P450表氧化酶 肿瘤坏死因子Α 内皮依赖性血管舒张反应 血管细胞粘附分子-1 

分 类 号：R54[医药卫生—心血管疾病]