OBJECTIVE: To study the activation of transforming growth factor (TGF)-beta(1)/Smads signal pathway in diabetic cardiomyopathy (DCM) and effects of valsartan thereon.
METHODS: 40 male Wistar rats were randomly divided into 3 groups: DCM group (n = 16, fed with high-calorie fat diet for 4 weeks, injected intraperitoneally with streptozocin so as to establish DCM model, and then perfused into the stomach with normal saline once daily since the injection of STZ for 16 weeks), valsartan group (n = 16, perfused into the stomach with valsartan at the dose of 30 mg/kg once a day for 16 weeks after the establishment of DCM model), and control group (n = 8, fed with normal diet and perfused into the stomach with normal saline once daily for 16 weeks). At the end of the experiment, the contents of fast blood-glucose (FBG), fast insulin (FIN), serum cholesterol, and triglyceride were detected, and insulin sensitivity index (ISI) was calculated. Cardiac catheterization was performed to measure the hemodynamics indexes: left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), and maximal rise/fall velocity of ventricular pressure (+/- dp/dt(max)), and the left ventricular diastolic function (T) was calculated. Pieces of myocardium tissue were taken out to undergo ultrastructural histopathological examination by transmission electron microscopy. The content of collagen was quantified by Masson three-color staining. Real-time RT-PCR and Western-blotting were used to detect the mRNA expression and protein expression of TGFbeta(1), TGFbetaRII, Smad2, Smad3, and Smad7.
RESULTS: By the end of experiment the levels of FBG, triglyceride, and cholesterol increased and the ISI decreased significantly in the DCM and valsartan groups (all P < 0.01). Compared with the valsartan and control groups the levels of LVEDP and T significantly increased, and the levels of LVSP and +/- dp/dt(max), significantly decreased (all P < 0.01); and the LVEDP of the valsartan group was significantly higher than that of the control group and the +/- dp/dt(max) of the valsartan group was significantly lower than that of the control group (P < 0.01). The volume of collagen in the myocardial tissue of the DCM group was 17% +/- 3%, significantly higher than that of the control group (11% +/- 3%, P < 0.01). The content of collagen in the myocardial tissue of the valsartan group was lower significantly than that of the DCM group. The levels of mRNA expression of TGFbeta(1), TGFbetaRII, Smad2, and Smad3 were 0.0126 +/- 0.0057, 0.0877 +/- 0.0272, 0.0884 +/- 0.0146, and 0.012 +/- 0.0048 respectively, all significantly higher than those of the control group (0.0054 +/- 0.0009, 0.0523 +/- 0.0218, 0.0413 +/- 0.0186, and 0.0064 +/- 0.0021 respectively, all P < 0.05 - 0.01). The ratios Smad2/Smad7 and Smad3/Smad7 of the DCM group were significantly higher than those of the control group (both P < 0.05). The protein levels of TGFbeta(1), P-Smad2, and P-Smad3 were 143 +/- 17, 212 +/- 43, and 151 +/- 32 respectively, all significantly higher than those of the control group (103 +/- 18, 107 +/- 21, and 89 +/- 17 respectively, P < 0.01). The P-Smad2/Smad7 and P-Smad3/Smad7 of the DCM group were significantly higher than those of the control group (both P < 0.05), The Smad2/Smad7 (or P-Smad2/Smads7) and Smad3/Smad7 (or P-Smad3/Smads7) of the valsartan group was significantly lower than those of the DCM group (both P < 0.05).
CONCLUSION: Activation of TGFbeta(1)/Smads signal pathway and imbalance between Smad2, 3 and Sma7 may be one of the mechanisms of myocardial interstitial fibrosis in DCM. Valsartan can prevent myocardium from damage by blocking the signal pathway.
