PPAR-gamma Agonist Attenuates Myocardial Fibrosis in a Type 2 Diabetic Rat Model

Ihm, Sang Hyun; Chang, Ki Yuk; Kim, Pum Joon; Kim, Hee Yeal; Baek, Sang Hong; Youn, Ho Joong; Seung, Ki Bae; Kim, Jae Hyung; Hong, Soon Jo; Choi, Kyu Bo

Abstract

BACKGROUND AND OBJECTIVES
Receptor for advanced glycosylation end product (RAGE) plays an important role in the development of myocardial fibrosis in diabetics. Activation of peroxisome proliferator activated receptor (PPAR)-gamma agonist, rosiglitazone, reduces the RAGE expression. We investigated whether rosiglitazone could prevent left ventricle (LV) diastolic dysfunction and attenuate the myocardial fibrosis in a type 2 diabetic rat model.
MATERIALS AND METHODS
Otsuka Long-Evans Tokushima Fatty (OLETF) rats were treated with rosiglitazone (20 mg/kg/d) for 20 weeks. At the age of 20 and 40 weeks, all rats underwent intraperitoneal glucose tolerance tests, hemodynamic studies and Doppler echocardiography. At the age of 40 weeks, the hearts were examined by performing histopathological and immunohistochemical analyses.
RESULTS
At the age of 40 weeks, rosiglitazone significant improved the parameters of the LV diastolic function such as the E/A ratio (treated vs. untreated: 1.7+/-0.1 vs. 1.5+/-0.1, p<0.05), the deceleration time and the isovolumic relaxation time in the OLETF rats, and this was correlated histologically to the reduced LV collagen volume fraction in the rosiglitazonetreated OLETF rats (3.2+/-1.3% vs. 5.7+/-2.0%, respectively, p<0.001). Rosiglitazone also significantly reduced the percentage of staining of the LV CTGF (7.4+/-2.5% vs. 15.4+/-4.7%, respectively, p<0.001) and RAGE (1.1+/-0.4% vs. 2.0+/-0.8%, respectively, p<0.001), as compared with the untreated OLETF rats.
CONCLUSION
These results suggest that rosiglitazone could prevent LV diastolic dysfunction and attenuate myocardial fibrosis in type 2 diabetic rats by its inhibition of the RAGE and CTGF expression. PPAR-gamma agonist may provide a potential therapeutic approach for diabetic heart disease.