缬沙坦和氟伐他汀对糖尿病心肌结缔组织生长因子基因表达的影响

The effect of valsartan and fluvastatin on the connective tissue growth factor expression in experimental diabetic cardiomyopathy

目的探讨缬沙坦、氟伐他汀及两药联合对糖尿病心肌病的保护作用及可能机制。方法构建链脲佐菌素诱导的SD大鼠糖尿病模型，实验分为糖尿病组、缬沙坦组（缬沙坦30mg·kg^-1·d^-1）、氟伐他汀组（氟伐他汀4mg·kg^-1·d^-1）、缬沙坦联合氟伐他汀组及正常对照组5组，每组8只，干预治疗12周。检测血糖、血脂、糖化血红蛋白及血流动力学。利用Van—Gieson染色、半定量RT—PCR和Western blot技术，检测左心室心肌胶原含量、结缔组织生长因子（CTGF）mRNA表达水平和Ⅰ型和Ⅲ型胶原、转化生长因子β（TGFβ）、CTGF蛋白表达的变化。结果糖尿病组大鼠左室心肌组织胶原含量明显增加，为正常对照组的2．1倍（P〈0．05），心脏／体重比率较正常对照组增加37％，存在心肌间质纤维化，左心室舒张功能减退（P〈0．05）。心肌组织CTGF mRNA和蛋白质表达水平均明显升高（P〈0．05），TGFβ、Ⅰ型和Ⅲ型胶原蛋白表达水平明显升高（P〈0．05），应用缬沙坦和氟伐他汀进行干预治疗后，上述异常均明显减轻（P〈0．05），联合治疗效果更佳（P〈0．05）。结论缬沙坦和氟伐他汀能够抑制CTGF及TGFβ的表达，使得Ⅰ型胶原和Ⅲ型胶原合成明显减少，抑制心肌纤维化，从而改善心功能。联合治疗有协同作用。

Objective To investigate the effect of valsartan and fluvastatin on the expression of connective tissue growth factor in early diabetic cardiomyopathy. Methods Forty male SD rats were randomly divided into five groups： normal control group, diabetic model（DM） group, DM ＋ valsartan group （30mg·kg^-1·d^-1）, DM＋fluvastatin group（4mg·kg^-1·d^-1） and DM＋ valsartan ＋ fluvastatin group（valsartan 30mg·kg^-1·d^-1 ＋ fluvastatin 4mg·kg^-1·d^-1）. After 12 weeks, miniature cardiac catheter was inserted into the left ventricle to conduct hemodynamic examination. Then myocardial tissue was collected and collagen content was detected with Van-Gieson staining. The levels of connective tissue growth factor（CTGF） mRNA expression in myocardium were determined using RT-PCR and Western blot was used to detect the protein expression of transforming growth factor （TGF） ~3, CTGF, collagen Ⅰ and Ⅲ. Results By the end of the experiment, left ventricular diastolic function was significantly decreased in the DM group in comparison with the control group（ P 〈 0. 05 ）. As compared with the normal control group, myocardial collagen content was significantly increased 1.1 fold （ P 〈 0. 05 ）, and the heart weight/body weight ratio was increased 37% in the DM group, but it was significantly reduced in the valsartan group and the fluvastatin group in comparison with the DM group（both P 〈0. 05）. The mRNA expression of CTGF was significantly higher in the DM group than in the control group, but it was significantly lower in the valsartan group and fluvastatin group than that in the DM group （ both P 〈 0. 05 ）. The values of protein expression of CTGF, TGF~, collagen I and llI were all significantly higher in the DM group than those in the control group （all P 〈 0. 05）. The protein expression of CTGF, TGFβ, collagen Ⅰ and Ⅲ in the valsartan group and flavastatin group was all significantly lower than that in the DM group （ P 〈 0. 05 ）. It was shown that treatment with valsatan or fluvastatin was effective for myocardial fibrosis in diabetic SD rats and valsartan combined with fluvastatin would be still better. Conclusion Valsatan and fluvastatin can reduce myocardial fibrosis, resulting in prevention of left ventricular remodeling and improvement of cardiac function in an experimental model of diabetic cardiomyopathy. The process was related to the inhibition of the overexpression of CTGF and TGFβ and reduction in cardiac extracellnlar matrix collagen content. It is also shown that a better result may be obtained with the coadministration of the two drugs than using one alone.