缬沙坦与氟伐他汀对实验性糖尿病心肌病中结缔组织生长因子表达的影响

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

作者信息

Wang Yong-Jian, Fu Guo-Sheng, Chen Fang-Ming, Wang Hui

机构信息

Department of Cardiology, Sir Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.

出版信息

Zhonghua Nei Ke Za Zhi. 2009 Aug;48(8):660-5.

PMID:19954059

Abstract

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 (30 mg x kg(-1) x d(-1)), DM + fluvastatin group (4 mg x kg(-1) x d(-1) ) and DM + valsartan + fluvastatin group (valsartan 30 mg x kg(-1) x d(-1) + fluvastatin 4 mg x kg(-1) x 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) beta, 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, TGFbeta, collagen I and III were all significantly higher in the DM group than those in the control group (all P < 0.05). The protein expression of CTGF, TGFbeta, collagen I and III in the valsartan group and fluvastatin group was all significantly lower than that in the DM group (P < 0.05). It was shown that treatment with valsartan or fluvastatin was effective for myocardial fibrosis in diabetic SD rats and valsartan combined with fluvastatin would be still better.

CONCLUSION

Valsartan 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 TGFbeta and reduction in cardiac extracellular 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.

摘要

目的

探讨缬沙坦和氟伐他汀对早期糖尿病性心肌病中结缔组织生长因子表达的影响。

方法

将40只雄性SD大鼠随机分为五组：正常对照组、糖尿病模型（DM）组、DM + 缬沙坦组（30 mg·kg⁻¹·d⁻¹）、DM + 氟伐他汀组（4 mg·kg⁻¹·d⁻¹）和DM + 缬沙坦 + 氟伐他汀组（缬沙坦30 mg·kg⁻¹·d⁻¹ + 氟伐他汀4 mg·kg⁻¹·d⁻¹）。12周后，插入微型心导管至左心室进行血流动力学检查。然后收集心肌组织，用Van-Gieson染色检测胶原含量。采用RT-PCR测定心肌中结缔组织生长因子（CTGF）mRNA表达水平，并用Western blot检测转化生长因子（TGF）β、CTGF、Ⅰ型和Ⅲ型胶原的蛋白表达。

结果

实验结束时，DM组左心室舒张功能较对照组显著降低（P < 0.05）。与正常对照组相比，DM组心肌胶原含量显著增加1.1倍（P < 0.05），心脏重量/体重比增加37%，但缬沙坦组和氟伐他汀组与DM组相比均显著降低（均P < 0.05）。DM组CTGF的mRNA表达显著高于对照组，但缬沙坦组和氟伐他汀组低于DM组（均P < 0.05）。DM组CTGF、TGFβ、Ⅰ型和Ⅲ型胶原的蛋白表达值均显著高于对照组（均P < 0.05）。缬沙坦组和氟伐他汀组CTGF、TGFβ、Ⅰ型和Ⅲ型胶原的蛋白表达均显著低于DM组（P < 0.05）。结果表明，缬沙坦或氟伐他汀治疗对糖尿病SD大鼠心肌纤维化有效，缬沙坦联合氟伐他汀效果更佳。