Study Of The Effects And Mechanisms Of Fluvastatin On Rats Of Dilated Cardiomyopathy

Objective: To assess the effects of fluvastatin on cardiac function, left ventricular remodeling in SD rats with adriamycin-induced dilated cardiomyopathy, and its mechanisms.Methods: (1)To establish adriamycin-induced cardiomyopathy rat models by intraperitoneal injection of adriamycin (2mg·kg^-1·week^-1) for 8 weeks. The model rats were divided randomly into 2 groups: fluvastatin group(F, n=10) and model control group(M, n=10), nomal rats group(C, n=10) served as control. (2)The left ventricular dimension at end-diastole (LVEDD) and left ventricular ejection fraction (LVEF) were measured with echocardiography at baseline and 8th weeks after intervention. Hemodynamic indexes including left end-ventricular diastolic pressure (LVEDP), maximum left ventricular developed pressure increase rate and decrease rate were measured at the 9th week. Histopathological characteristics were observed in HE, VG, then left ventricular relative weight(LVRW) and collagen volume fractions(CVF) were calculated. (3)The myocardial total antioxidation capacity(TAOC) and concentration of malondialdehyde(MDA) were measured with colorimetric analysis. (4)Contents of tumor necrosis factor-a(TNF-a), interleukin-6(IL-6) and interleukin-1(?)(IL-1(?)) were determined by radioimmunoassay from venous serum. (5)Protein expression of Bax and Bcl-2 genes was determined by Western blot, mRNA expression of Fas,Fas-L,Bax and Bcl-2 genes was evaluated by RT-PCR analysis.determined by Western blot, mRNA expression of Fas,Fas-L,Bax and Bcl-2 genes was evaluated by RT-PCR analysis.Results: (1)Compared with the normal rats, LVEDD of the DCM rats was significantly increased[(6.88±0.20)mm vs (5.85±0.29)mm, P<0.05] and LVEF[(74.6±2.8)% vs (88.6±2.9)%, P<0.05] was reduced in adriamycin-induced cardiomyopathy rat models. (2)During the course of treatment for 8 weeks, LVEDD in the F group was lower than M group [(6.1±0.4)mm vs (6.9±0.2)mm, P<0.05], while LVEF in the F groups was higher than M group [(83.9±1.9)% vs (75.6±2.5)%, P<0.05]. (3)Compared with the M group, + dp/dt_max of the F group was increased[(4475.5±337.4)mmHg/s vs (3551.5±256.4)mmHg/s, P<0.05], and - dp/dt_max of the F group was also significantly increased [(-3497.9±288.6)mmHg/s vs (-2785.8±215.0), P<0.05]. (4)In comparison with the C group, left ventricular relative weight(LVRW) of the M group was significantly increased[(2.44±0.13) vs (1.74±0.11), P<0.05], collagen volume fraction (CVF) was significantly increased[(11.9±0.6)% vs (2.5±0.3)%, P<0.05]. Compared with the M group, LVRW of the F group was significantly decreased[(1.96±0.12) vs (2.44±0.13), P<0.05], CVF was significantly decreased[(5.8±1.4)% vs (11.9±0.6)%, P<0.05]. (5)In comparison with the C group, MDA of the M group was significantly increased [(1.21±0.12)nmol/mg vs (0.48±0.03)nmol/mg, P<0.05], while TAOC of the M group was significantly decreased[(0.75±0.08)U/mg vs (1.52±0.11)U/mg, P<0.05]. Compared with the M group, MDA of the F group was significantly decreased[(0.75±0.06)nmol/mg vs (1.21±0.12)nmol/mg, P<0.05], while TAOC of the F group was significantly increased[(1.13±0.10)U/mg vs (0.75±0.08)U/mg, P<0.05]. (6) In comparison with the C group, contents of TNF-a, IL-6 and IL-1(?) in the M group were significantly increased[(18.36±2.21)fmol/ml vs 0 P<0.05], [(0.33±0.04)ng/ml vs (0.16±0.03)ng/ml P<0.05], [(0.35±0.03)ng/ml vs (0.17±0.02)ng/ml, P<0.05]. Compared with the M group, contents of TNF-a, IL-6 and IL-1(?) in the F group were significantly decreased [(12.56±2.03)fmol/ml vs (18.36±2.21)fmol/ml, (0.24±0.02)ng/ml vs (0.33±0.04)ng/ml, (0.26±0.04)ng/ml vs (0.35±0.03)ng/ml, P<0.05]. (7)The mRNA expression of Fas, Fas-L and Bax in M group were higher than C group[(0.67±0.06) vs (0.22±0.04), P<0.05], [(0.71±0.06) vs (0.26±0.05), P<0.05], [(0.94±0.11) vs (0.34±0.04), P<0.05]. While the mRNA expression of Bcl-2 in M group was lower than C group[(0.32±0.04) vs (0.78±0.06), P<0.05]. The mRNA expression of Fas, Fas-L and Bax in the F group were lower than M group[(0.39±0.03) vs (0.67±0.06), P<0.05], [(0.42±0.03) vs (0.71±0.06), P<0.05], [(0.52±0.05) vs (0.94±0.11), P<0.05]. While the mRNA expression of Bcl-2 in F group was higher than M group[(0.56±0.06) vs (0.32±0.04), P<0.05]. (8) Protein expression of Bax gene in M group was higher than C group[(0.72±0.12) vs (0.21±0.04), P<0.05], while Bcl-2 gene in M group was lower than C group[(0.31±0.04) vs (0.64±0.07), P<0.05]. Protein expression of Bax gene in F group was lower than M group[(0.43±0.08) vs (0.72±0.12), P<0.05], while Bcl-2 gene in F group was higher than M group[(0.46±0.06) vs (0.31±0.04), P<0.05].Conclusion: Fluvastatin can improve cardiac function, attenuate left ventricular remodling in SD rats with adriamycin induced dilated cardiomyopathy. The mechnisms include suppressing oxidative stress, reducing inflammatory cytokines and inhibiting cardiac myocyte apoptosis of fluvastatin.