Combination of a peroxisome proliferator-activated receptor-gamma agonist and an angiotensin II receptor blocker attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats

Aims/Introduction: We aimed to examine the effect of an angiotensin II receptor blocker (ARB), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, and their combination on myocardial fibrosis and function in type 2 diabetic rats. Materials and Methods: Five male Long-Evans Tokushima Otsuka (LETO) rats and 20 male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used. OLETF rats were assigned to four groups (n = 5 per group) at 28 weeks-of-age: untreated, losartan-treated, rosiglitazone-treated and combination-treated. The ARB, losartan, was administered at a dose of 5 mg/kg/day, and the PPAR-gamma agonist, rosiglitazone, was administered at a dose of 3 mg/kg/day by oral gavage for 12 weeks. Urine and blood samples were collected, and two-dimensional echocardiograms and strain rate imaging were obtained at 28 and 40 weeks. Cytokines were evaluated by reverse transcriptase polymerase chain reaction, and histological analysis was carried out at 40 weeks. Results: At 40 weeks, the global radial strains of the losartan-treated (55.7 ± 4.5%, P = 0.021) and combination-treated groups (59.3 ± 6.7%, P = 0.001) were significantly higher compared with the untreated OLETFs (44.3 ± 10.5%). No difference was observed when compared with LETO rats. Although the rosiglitazone-treated group showed a better metabolic profile than the untreated OLETF group, there was no difference in the global radial strain (49.8 ± 6.0 vs 44.3 ± 10.5, P = 0.402). The expression of pro-inflammatory cytokines, and collagen type I and III were consistently attenuated in the losartan-treated and combination-treated OLETF groups, but not in the rosiglitazone-treated group. Conclusions: A combination of rosiglitazone and losartan attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats.