gms | German Medical Science

Background: Emerging evidence suggests that statins exert beneficial effects beyond those predicted by their cholesterol-lowering actions. We investigated if low dose atorvastatin (Ator) improves left ventricular (LV) function in an experimental model of diabetic cardiomyopathy.

Methods: DM was induced by a single injection of streptozotozin (STZ) (70 mg/kg, i.p.) in 8 weeks old Sprague Dawley (SD) rats. Diabetic rats were treated with Ator (50 mg/kg/day; per gavage) or with vehicle for 6 weeks. Age-matched non-diabetic SD rats were used as controls. LV function was analyzed by a Millar tip catheter. Expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, cellular adhesion molecules (CAM)s, leukocyte infiltration and collagen content was quantified by digital image analysis and/or real-time PCR. Rac1- and RhoA-GTPase activity was determined by Rac1 GST-PAK and Rhotekin pull-down assays, respectively. p38 MAPK and phospho-p38 MAPK were quantified by Western Blot.

Results: Diabetes was associated with increased myocardial TNF-alpha, IL-1beta, ICAM-1 and VCAM-1 expression and increased leukocyte infiltration. Moreover, cardiac collagen I and III expression and total cardiac collagen content was increased in STZ diabetic rats compared to non-diabetic controls. These findings correlated with impaired left ventricular function. Ator-treatment was associated with both reduced intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function. This effect was associated with reduction of Rac1- and RhoA-GTPase activity to levels similar as in non-diabetic SD rats and with a 3.8-fold (p<0.05) decrease in STZ-diabetes-induced p38 MAPK activity. Dyslipidemia was not affected by Ator-treatment.

Conclusion: Inhibition of Rac1- and RhoA-GTPase activity by low dose Ator reduces intramyocardial inflammation and myocardial fibrosis, partly mediated by reduction in p38 MAPK activity, resulting in improved LV function in STZ diabetic rats.