PP.21.03] DIPEPTIDYL PEPTIDASE 4 INHIBITOR ATTENUATES OBESITY INDUCED MYOCARDIAL FIBROSIS BY THE UP-REGULATION OF REGULATORY T CELLS

Abstract

Objective: Obesity-induced myocardial fibrosis may lead to diastolic dysfunction and ultimate heart failure. The immune system play a pivotal role in the pathogenesis of obesity-induced target organ damages. Dipeptidyl peptidase 4 (DPP4) inhibitor (antidiabetic drug) is known to be an immune modulator in cardiac inflammation. We hypothesized that DPP4 inhibitors induce regulatory T cell (Tregs) activation in the myocardium of a diet-induced obesity model, which reduces myocardial fibrosis. Design and method: We assessed the extent of Treg response and fibrosis within the myocardium. 8 week-old male spontaneously hypertensive rats (SHRs) fed with high fat diet (HFD) were randomized to either DPP4 inhibitor (MK-0626; SHR HFD-M) or control groups (SHR HFD). At the age of 20 weeks, all rats underwent hemodynamic and metabolic studies and Doppler echocardiography. After scarify, we measured TGF-b1, collagen, Tregs, transcription factor (Foxp3) and interleukin-10 (IL-10) in the heart and/or mediastinal lymph nodes. Results: Compared with wistar Kyoto rats (WKYs; normal control), SHRs fed with HFD developed more intense degree of hypertension, hyperglycemia, and hyperlipidemia but DPP4 inhibitor significantly improved metabolic and hemodynamic parameters. Echocardiogram showed that DPP4 inhibitors improved left ventricular (LV) diastolic dysfunction (E/A ratio, SHR HFD vs. SHR HFD-M; 1.52 ± 0.30 vs. 1.94 ± 0.28, p < 0.05) but fail to reduce LV hypertrophy and systolic function. In line with these findings, DPP4 inhibitor significantly reduced myocardial fibrosis and collagen production of the myocardium along with the suppression of TGF-b1. In addition, DPP4 inhibitors increased Tregs and the expression of IL-10 and FoxP3 in the heart and mediastinal lymph nodes of SHR-HFD. Conclusions: We found that diet-induced obesity typically showed a constellation of LV diastolic dysfunction, exacerbated myocardial fibrosis and down-regulation of Tregs pathway, and DPP4 inhibition improved LV diastolic dysfunction by attenuating myocardial fibrosis along with the up-regulation of Tregs pathway. These findings suggest that DPP4 inhibition induce Tregs activation leading to reduced myocardial fibrosis and improved diastolic dysfunction of LV in a model of diet-induced obesity.