Abstract 10852: Sitagliptin Reduces Myocardial Fibrosis and Hypertrophy, Enhances Ppard Activation and Improves Diastolic Function in Experimental Type-2 Diabetes.
Aim: To study the role of Sitagliptin in cardiac fibrosis and hypertrophy associated to type-II Diabetes (DM2)
Background: Major characteristics of the DM2 myocardium are fibrosis and hypertrophy, and their related-molecular mechanisms need to be investigated. The anti-diabetic Sitagliptin (a dipeptidyl peptidase-4 inhibitor) improves the insulin response in DM2 patients, but its cardiac effects have not been unveiled
Methods: DM2 rats (Goto-Kakizaki) were treated with Sitagliptin (100 mg/Kg/day) for 10 weeks (n=10). Untreated DM2 and Wistar were also analyzed. Cardiac function was assessed by Echo-Doppler, and plasma and left ventricles were collected for analysis. H9c2 cardiomyocyte cell line was use for in vitro assays
Results: DM2 rats presented hyperglicemia and hyperlipidemia. Blood pressure was normal. Sitagliptin reduced plasma levels of glucose, triglycerides, cholesterol and HDL lipoproteins. By Echo-Doppler, DM2 rats showed an increase of septum thickness and prolonged deceleration time, suggesting diastolic dysfunction. Moreover, DM2 myocardium showed interstitial fibrosis and hypertrophy. Sitagliptin markedly reduced the deceleration time and both cardiac fibrosis and hypertrophy. In this sense, DM2 hearts presented increased pro-fibrotic [Transforming growth factor (TGFβ), Connective Tissue Growth Factor (CTGF), extra-cellular matrix protein fibronectin and metalloprotease inhibitor TIM-1] and hypertrophic [Atrial natriuretic peptide (ANP) and Cardiotrophin-1 (CT-1)] factors, and down-regulated peroxisome proliferator activating receptor-delta (PPARd) activation. Fibronectin, TIM-1, ANP, CT-1 and PPARd levels were restored in Sitagliptin-treated rats. In cultured cardiomyocytes, co-stimulation with high concentration of glucose and palmitic acid (saturated fatty-acid) diminished PPARd in correlation to stimulated pro-fibrotic (TGFβ, CTGF and fibronectin) factors
Conclusions: In experimental DM2, TGFβ/CTGF and CT-1 may regulate cardiac fibrosis and hypertrophy through PPARd reduction. In this sense, the anti-hypertrophic effect induced by Sitagliptin may be related to PPARd activation
- © 2010 by American Heart Association, Inc.