Hydroxymethyl Glutaryl Coenzyme A Reductase Inhibitor Fluvastatin Ami Rat Ventricular Remodeling And Related Mechanisms,

Background A phagocyte-type nicotinamide adenine dinucleotide 3-phosphate (reduced form) (NADPH) oxidase complex is a major source of ROS in the vasculature and is implicated in the pathophysiology of hypertension and atherosclerosis. In myocardium the increased oxidative stress due to excessive production of ROS may be involved in the pathophysiology of congestive heart failure. The expression of NADPH oxidase in the myocardium and its product O₂ may influence the ventricular remodeling and the cardiac function after myocardial infarction.Objectives This study was designed to investigate whether A phagocyte-type NADPH oxidase is over-expressed in the heart of myocardial infarction rats and whether it contributes to superoxide anionin production in myocardium. Methods Myocardial infarction Sprague-Dawley rats were established by left anterior descending coronary artery ligation.8 weeks after operation, Doppler echocardiography, hemodynamic and histomorphometry study were performed to analysis the ventricular remodeling; the level of thiobarbituric acid reactive substance in the plasma and myocardium were analyzed, and the distribution of O₂ were also examined with laser scanning confocal microscope. The expression of p22phox in mRNA and protein level were detected with RT-PCR and immunohistochemistry.Results After myocardial infarction, the procedure of left ventricular remodeling was significant, the level of thiobarbituric acid reactive substance increased in the plasma and non-infarcted myocardium of myocardial infarction rats. Both theexpression of p22-phox in mRNA and protein level and the distribution of O₂increased in infracted and non-infracted myocardium of rats.Conclusion Our results suggest that the expression of NADPH oxidase and itsproducts O₂ may take part in left ventricular remodeling through oxidative stressesmechanism after myocardial infarction.Part II The Influence of Fluvastatin on Left Ventricular Remodeling in Myocardial Infarction RatsABSTRACTObjective To clarify whether long-term administration of 3-hydroxy-3- methyl-lglutaryl coenzyme A (HMG-CoA) reductase inhibitors, fluvastatin, can improve ventricular remodeling in myocardial infarction rats, and investigate its correlated mechanism.Methods Sprague-Dawley rats were subjected to anterior descending branch coronary artery ligation and were treated for 8 weeks with fluvastatin (20 mg-kg^-1d^-1, PO) or distilled water. Doppler echocardiography, hemodynamic study, cardiac histomorphometry were used to estimate the ventricular remodeling and cardiac function, laser scanning confocal microscope was used to definite the distribution of O₂ and NO. RT-PCR and Immunohistochemistry were used to definite the distribution of NOS2 and p22phox in mRNA and protein level. The level of total cholesterol and TBARS, GSH-PX, nitrogen monoxide were detected too.Results Administration of fluvastatin meliorate left ventricular remodeling without affecting the infarcted size (40±6 vs. 42±5%), P >0.05. The left ventricular end-diastole pressure (18.24±6.58 vs. 10.74±4.71mmHg), right ventricular relative weight (0.92±0.19 vs. 0.71±0.13)g-kg^-1 and left ventricular posterior wall thick (3.04±0.28 vs. 2.60±0.36mm)were decreased (P <0.05, <0.01); the left ventricular ejection fraction were not influenced, the relative lung weight (5.79±2.92 vs. 3.69±0.68g-kg^-1, P <0.05) and the left atrium diameter were reduced (0.55±0.12 vs. 0.45±0.04mm, P <0.01); also the level of TBARS in the plasma (8.64±0.59 vs. 7.71±0.66U-dL^-1, P<0.05) and myocardium (3.12±0.38 vs. 1.93±0.40 ng-ug^-1pro, P <0.01)were descreased, and the over-expressed NO(436.87±47.22 vs.313.78±34.35 mg·dL^-1, P <0.05) were inhibited and increased the expression of GSH-PX(66.13±8.31 vs. 79.78±2.38 mg-dL^-1, P<0.01). After AMI, the expression and the activity of 0₂ originated primarily from NADPH oxidase subunit p22phox were enhanced; NOS2 and its products, NO, over-expressed, too; both of which were inhibited by the intervention of fluvastatin.Conclusion...