Objective To investigate effect of fluvastatin on myocardial interstitial fibrosis and cardiac function in diabetic rats.
Methods 24 male SD rats were randomly divided into three groups: normal control (n=8), untreated and STZ-induced diabetic rats (n=8) and diabetic rats treated with fluvastatin (n=8). DM was induced in male SD rats with a single intraperitoneal (i.p.) injection of streptozotocin 50 mg/kg dissolved in 20 mM citrate buffer (pH 4.5) overnight. Tail vein blood glucose was measured 72 h later and those with plasma glucose levels ≥16.7 mmol/l were considered to be diabetic. Control rats were injected 1 ml/kg body weight of 20 mM citrate buffer (pH 4.5) vehicle, and diabetic rats were treated with fluvastatin (10 mg/kg administered orally, n=8). Fluvastatin were dissolved in sterile water, and administered every day via stomach tube. These rats were housed for 12 weeks with daily general checking. After 12 weeks intervention, miniature cardiac catheter was inserted into the left ventricle to conduct haemodynamic examination. Then, myocardium tissues were collected, collagen content was detected by picro-sirius red staining, immunohistochemistry was used to detect protein expression of fibronectin, real-time RT-PCR was used to detect the mRNA expression of CTGF and Western blotting was used to detect the protein expression of CTGF. RhoA activity in LV myocardial tissue of rats was determined by pull down assay.
Results By the end of the experiment, the left ventricular systolic pressure (LVSP)(97±12 mm Hg vs 131±21 mm Hg) and maximum rate of left ventricular (LV) pressure rise and fall (+dP/dt max and -dP/dt max) (4410±332 mm Hg/s vs 6465±442 mm Hg/s and −4326±365 mm Hg/s vs-6432±426 mm Hg/s) were significantly lower and left ventricular end diastolic pressure (LVEDP)(16.2±3.2 mm Hg vs 4.8±1.2 mm Hg) were significantly higher in the diabetic group compared to the control group (all p<0.01). Moreover, in LV myocardial tissue of diabetic rats the collagen content (4.2%±0.36% vs 6.4%±0.33%, p<0.01), fibronectin (3.12±0.30 vs 0.95±0.33, p<0.01), mRNA and protein expression of CTGF (0.86±0.10 vs 1.37±0.24 and 0.48±0.13 vs 1.26±0.22, p<0.01) and the activity of RhoA (1.72±0.21 vs 1.1±0.1, p<0.01) were all significantly increased compared to the control rats. Administration of fluvastatin obviously improved the cardiac function of diabetic rats, attenuated fibronectin expression, mRNA and protein expression of CTGF and the activity of RhoA in LV myocardium of diabetic rats.
Conclusions Our data demonstrate that fluvastatin attenuates cardiac dysfunction and myocardial interstitial fibrosis of diabetic rat by inhibiting activity of RhoA to down-regulate the over-expression of CTGF, and Rho/Rho-kinase pathway may be an important target in the treatment of diabetic cardiomyopathy.
- myocardial interstitial fibrosis
- cardiac function
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