LAUSR

BACKGROUND Cardiac thyrotropin-releasing hormone (TRH) is a tripeptide with still unknown functions. We demonstrated that the left ventricle (LV) TRH system is hyperactivated in spontaneously hypertensive rats and its inhibition prevented cardiac hypertrophy and fibrosis. Therefore, we evaluated whether in vivo cardiac TRH inhibition could improve myocardial function and attenuate ventricular remodeling in a rat model of myocardial infarction (MI). METHODS AND RESULTS In Wistar rats, MI was induced by a permanent left anterior descending coronary artery ligation. A coronary injection of a specific siRNA against TRH was simultaneously applied. The control group received a scrambled siRNA. Cardiac remodeling variables were evaluated one week later. In MI rats, TRH inhibition decreased LV end-diastolic (1.049±0.102 vs. 1.339±0.102 ml, p<0.05), and end-systolic volumes (0.282±0.043 vs. 0.515±0.037 ml, p<0.001), and increased LV ejection fraction (71.89±2.80 vs. 65.69±2.85 %, p<0.05). Although both MI groups presented similar infarct size, siRNA-the TRH treatment attenuated the cardiac hypertrophy index and myocardial interstitial collagen deposition in the peri-infarct myocardium. These effects were accompanied by attenuation in the rise of TGFβ, collagen I, and III and also the fetal genes (ANP, BNP, and βMHC) expression in the peri-infarct region. Besides, the expression of Hif1α and VEGF significantly increased compared to all groups. CONCLUSIONS Cardiac TRH inhibition improves LV systolic function and attenuates ventricular remodeling after MI. These novel findings support the idea that TRH inhibition may serve as a new therapeutic strategy against the progression of heart failure.