Abstract: Abstract: Objective To investigate the effect of telmisartan on the expression of peroxisome proliferator activated receptor gamma (PPARγ) and its regulation in myocardial remodeling in spontaneously type 2 diabetic male Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed with high-fat diet. Methods Twenty-eight four-week-old male OLETF rats were fed with high-fat diet. From 22-week of age, the pre-diabetic OLETF rats were randomly assigned to three groups:telmisartan-treated group [O-T group, 5 mg/(kg·d), n=10], pioglitazone-treated group [O-P group, 10 mg/(kg·d), n=8] and untreated group ( O-C group, equal volume of normal saline, n=10),continuously administration for 22-week. Twelve sex and age matched Long-Evans Tokushima Otsuka (LETO) rats were used as control (LETO group). At 22 and 48-week of age,the glucose tolerance of the rats was assessed by the oral glucose tolerance test (OGTT). At 48 weeks of age, five rats were randomly selected from each group, and clamp experiments were carried out. The glucose infusion rate from 60 min to 120min (GIR60-120) was measured. All rats were sacrificed and the myocardial tissues were dissected. The ratio of heart weight to body weight (HW/BW) was calculated. Blood samples were collected, and serum PPARγ, tumor necrosis factor-alpha(TNF-α), interleukin-6 (IL-6) and adiponectin were measured using ELISA and radioimmunoassay. The mRNA expressions of IL-6, PPARγ1 and PPARγ2 were measured by real-time PCR. The protein expression levels of PPARγ, adiponectin, IL-6 and NF-κB were determined by Western blot assay. The myocardial pathological changes were observed under light microscope(HE staining, Masson staining and PAS staining), and ultrastructural changes were observed under transmission electron microscope. Results At 22-week of age, neither type 2 diabetes mellitus (T2DM) nor IGT were found in three groups. At 48-week of age, T2DM was found in seven rats of O-C group, and IGT was found in two rats. T2DM was found in one rat of O-C group, and IGT was found in three rats. Neither T2DM nor IGT was found in the other two groups. GIR60-120 and HW/BW were all significantly lower in the O-P group and O-T group than those of the O-C group at 48-week of age (P＜0.05).Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly lower in O-T group than those in other three groups (P＜0.05). Compared with the O-C group, the serum levels of PPARγ and adiponectin were significantly upregulated, whereas the serum levels of IL-6 and TNF-α were down-regulated by telmisartan administration in O-T group(P＜0.05). There were no significant differences in the above indexes between O-P and O-T groups. The results of real-time PCR and Westen blot assay showed that the mRNA expression of PPARγ1 was increased, and IL-6 expression decreased in O-T group compared with those of O-C group. The protein expressions of PPARγ and adiponectin were increased, and protein expressions of NF-κB and IL-6 were significantly decreased in O-P group and O-T group compared with those of OC group (P＜0.05). In the O-C group, the arrangernent of myocardial cells was irregular, myocardial fibers were swollen, a large amount of fibrotic tissue in the myocardial interstitium, and glycogen accumulation under light and electron microscope. Besides, myofibril breakage and perinuclear space expansion, myocardial mitochondria were apparently damaged or even dissolved. Compared with the O-C group, myocardial fibers arranged neatly, no obvious glycogen deposition and the ultrastructural changes of myocardium were obviously reduced in O-T group and O-P group.Conclusion Telmisartan can increase the expression level of PPARγ in the serum and myocardial tissue, reduce myocardial fibrosis and alleviate cardiac remodeling in the high-fat-diet OLETF rats.

Key words: rats, inbred OLETF, ventricular remodeling, diabetes mellitus, type 2, PPARγ, telmisartan