Combination of a peroxisome proliferator-activated receptor-gamma agonist and an angiotensinII receptor blocker attenuates myocardial fibrosis and dysfunction in type2 diabetic rats.

Abstract

We aimed to examine the effect of an angiotensinII receptor blocker (ARB), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, and their combination on myocardial fibrosis and function in type2 diabetic rats. 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 28weeks-of-age: untreated, losartan-treated, rosiglitazone-treated and combination-treated. The ARB, losartan, was administered at a dose of 5mg/kg/day, and the PPAR-gamma agonist, rosiglitazone, was administered at a dose of 3mg/kg/day by oral gavage for 12weeks. Urine and blood samples were collected, and two-dimensional echocardiograms and strain rate imaging were obtained at 28 and 40weeks. Cytokines were evaluated by reverse transcriptase polymerase chain reaction, and histological analysis was carried out at 40weeks. At 40weeks, 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 typeI and III were consistently attenuated in the losartan-treated and combination-treated OLETF groups, but not in the rosiglitazone-treated group. A combination of rosiglitazone and losartan attenuates myocardial fibrosis and dysfunction in type2 diabetic rats.