Al-Ruzzeh Sharif, Schmidt Ilona, Nakamura Koki, Chester Adrian, Ilsley Charles, Amrani Mohamed
Department of Cardiothoracic Surgery, Harefield Hospital, Middlesex UB9 6JH, United Kingdom.
Tex Heart Inst J. 2004;31(2):127-31.
The anti-atherogenic properties of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been well established in several circulatory beds. Increasing evidence suggests that statins may help attenuate ischemia-reperfusion injury, a beneficial effect that may be related to the antioxidant capabilities of statins; however, this remains controversial. We performed this study to determine whether the HMG-CoA reductase inhibitor cerivastatin can prevent oxidative stress-induced injury in cultured human aortic endothelial cells (HAEC). The HAEC were subjected to oxidative stress in the absence and presence of increasing concentrations of cerivastatin (50 nM-1,000 nM). Oxidative stress was induced by increasing concentrations of hydrogen peroxide or endogenous superoxide anions generated by the inhibition of superoxide dismutase using diethylthiocarbamate (10 mM). Cell viability and mitochondrial activity were measured by mitochondria-dependent 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) conversion. Cell morphology was also examined using light microscopy. Exposing HAEC to cerivastatin for 24 hours had no effect on cell viability using both cell morphology and MTT conversion: the HAEC incubated in 100 nM cerivastatin had 90% +/- 2.2% viability of the control. As expected, hydrogen peroxide produced a concentration-dependent decrease in cell viability. Varying concentrations of cerivastatin pretreatment for < or = 18 hours showed no protection of HAEC against hydrogen peroxide-induced injury. As a positive control, the prototype antioxidant N-acetyl-L-cysteine was cytoprotective even with the highest hydrogen peroxide concentration. Neither cerivastatin nor N-acetyl-L-cysteine protected HAEC against diethylthiocarbamate-induced oxidative injury at any concentration. In this study, cerivastatin did not protect cultured HAEC against oxidative stress induced by hydrogen peroxide or diethylthiocarbamate.
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）的抗动脉粥样硬化特性已在多个循环系统中得到充分证实。越来越多的证据表明，他汀类药物可能有助于减轻缺血再灌注损伤，这种有益作用可能与他汀类药物的抗氧化能力有关；然而，这一点仍存在争议。我们进行这项研究以确定HMG-CoA还原酶抑制剂西立伐他汀是否能预防氧化应激诱导的人主动脉内皮细胞（HAEC）损伤。在有无不同浓度（50 nM - 1000 nM）西立伐他汀存在的情况下，使HAEC遭受氧化应激。通过增加过氧化氢浓度或使用二乙硫代氨基甲酸盐（10 mM）抑制超氧化物歧化酶产生内源性超氧阴离子来诱导氧化应激。通过线粒体依赖性的3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四氮唑（MTT）转化来测量细胞活力和线粒体活性。还使用光学显微镜检查细胞形态。使用细胞形态学和MTT转化法，将HAEC暴露于西立伐他汀24小时对细胞活力没有影响：在100 nM西立伐他汀中孵育的HAEC具有对照细胞90%±2.2%的活力。正如预期的那样，过氧化氢导致细胞活力呈浓度依赖性下降。在≤18小时内用不同浓度西立伐他汀预处理未显示对HAEC有针对过氧化氢诱导损伤的保护作用。作为阳性对照，即使在过氧化氢浓度最高时，原型抗氧化剂N-乙酰-L-半胱氨酸也具有细胞保护作用。在任何浓度下，西立伐他汀和N-乙酰-L-半胱氨酸均未保护HAEC免受二乙硫代氨基甲酸盐诱导的氧化损伤。在本研究中，西立伐他汀不能保护培养的HAEC免受过氧化氢或二乙硫代氨基甲酸盐诱导的氧化应激损伤。
