氟伐他汀抗氧化改善心肌梗死大鼠心室重塑

目的:探讨氟伐他汀长期应用对SD大鼠心肌梗死(AMI)心室重塑过程的影响及其机制.方法:结扎雄性大鼠左冠状动脉前降支,复制心肌梗死模型,将大鼠分为2组,AMI组(n=7)以蒸馏水灌胃,氟伐他汀组(n=8)以氟伐他汀20 mg·kg-1·d-1灌胃;另设假手术2组,分别以蒸馏水和氟伐他汀灌胃.8周后心脏超声、血液动力学、心脏形态学分析;检测血浆总胆固醇(Tch)、一氧化氮(NO)、脂质过氧化物(LPO)、谷胱甘肽过氧化物酶(GPx)和心肌LPO水平;激光共聚焦显微镜检测超氧阴离子和NO的分布;RT-PCR、免疫组化检测诱导型一氧化氮合酶(NOS2)、p22phox的mRNA和蛋白水平表达.结果:与AMI组比较,氟伐他汀组左室舒张末压降低(18.24±6.58 vs 10.74±4.71)mmHg,P<0.05]、右室相对重量减轻(0.92±0.19 vs 0.71±0.13)g/kg,P<0.05]、左室后壁厚度减少(3.04±0.28 vs 2.60±0.36)mm,P<0.05];AMI后射血分数无影响,但肺相对重量减轻(5.79±2.92 vs 3.69±0.68)g/kg,P<0.05];血浆和心肌LPO水平降低(8.64±0.59 vs 7.71±0.66)μmol/L,P<0.05;(3.12±0.38 vs 1.93±0.40)ng/μg.pro,P<0.01],NO的过度表达抑制和GPx水平增加(436.87±47.22 vs 313.78±34.35)mg/dl,P<0.01;(66.13±8.31 vs 79.78±2.38)mg/dl,P<0.05].氟伐他汀干预后增加NOS2、p22phox mRNA和蛋白水平的表达均下降(P<0.01).血浆总胆固醇水平减低,但无显著性差异(59.40±14.15 vs 48.30±8.83) mg/dl,P>0.05].结论:氟伐他汀参与了改善大鼠心肌梗死后心室重塑过程,其中可能包括抗氧化机制.

Influence of fluvastatin on left ventricular remodeling after myocardial infarction in rats

OBJECTIVE: To investigate the effect of long-term administration of fluvastatin on improvement of ventricular remodeling of rats after myocardial infarction and its mechanism. METHODS: Sprague-Dawley rats were subjected to ligation in anterior descending branch of coronary artery and treated with fluvastatin (20 mg.kg(-1) d(-1)) or distilled water for 8 weeks. Doppler echocardiography, hemodynamic study and cardiac histomorphometry were used to estimate the ventricular remodeling and cardiac function. Laser scanning confocal microscope was used to definite the distribution of superoxide anion (O(2)(*-)) and nitrogen monoxide. RT-PCR and immunohistochemistry were used to detect the expression of NOS2 and p22phox in mRNA and protein level. The level of lipid peroxidation, glutathione peroxidase, nitrogen monoxide and total cholesterol were detected too. RESULTS: Administration of fluvastatin ameliorated left ventricular remodeling without affecting the infarct size (40 +/- 6 vs 42 +/-5)%, P>0.05]. The level of left ventricular end-diastolic pressure (18.24 +/-6.58 vs 10.74 +/-4.71) mmHg, P<0.05], right ventricular ameliorated relative weight (0.92 +/-0.19 vs 0.71 +/-0.13) g/kg, P<0.05], the thickness of left ventricular posterior wall (3.04 +/-0.28 vs 2.60 +/-0.36) mm, P<0.05] decreased after fluvastatin treatment. The left ventricular ejection fraction was not influenced, the relative lung weight and the left atrium diameter reduced (5.79 +/-2.92 vs 3.69 +/-0.68) g/kg, (0.55 +/-0.12 vs 0.45 +/-0.04) mm, P<0.05]; the expressions of LPO in the plasma and myocardium (8.64 +/-0.59 vs 7.71 +/-0.66) U/dl, P<0.05; (3.12 +/-0.38 vs 1.93 +/-0.40) ng/microg.pro, P<0.01] were reduced, and the overexpressed NO was inhibited (436.87 +/-47.22 vs 313.78 +/-34.35) mg/dl, P<0.01], but the expression of GPx increased (66.13 +/-8.31 vs 79.78 +/-2.38) mg/dl, P<0.01]. The expression of O(2)(*-) and the activity of NADPH oxidase subunit p22phox increased; NOS2 and its products NO were over-expressed too. CONCLUSION: Ventricular remodeling and hemodynamics are improved profoundly in MI rats treated with fluvastatin. The effect of antioxidative stress of fluvastatin might be involved in the mechanism.