Cardiac TRH Partly Mediates Angiotensin II-induced Fibrotic and Hypertrophy Effects in "in vivo" and "in vitro" Models

GARCIA, SILVIA INES; PERES DIAZ, LUDMILA; AISICOVICH, MAIA; SCHUMAN, MARIANO LUIS; LANDA, MARIA SILVINA

Washington DC

Congreso; Council of High Blood Pressure, AHA; 2015

Abstract:Cardiac TRH (cTRH) is overexpressed in the hypertrophied ventricle (LV) of theSHR. Additionally in vivo siRNA-TRH treatment induced downregulation of LV-TRHpreventing cardiac hypertrophy and fibrosis demonstrating that TRH is involvedin hypertrophic and fibrotic processes. Moreover, in a normal heart, theincrease of LV TRH expression alone could induce structural changes wherefibrosis and hypertrophy could be involved, independently of any other systemalterations.Is well-known the cardiac hypertrophy/ fibrotic effects induced by AII, raisingthe question of whether specific LV cTRH inhibition might attenuates AIIinduced cardiac hypertrophy and fibrosis in mice.We challenged C57 mice with AII (osmotic pumps,14 days; 2 mg/kg) to inducecardiac hypertrophy vs saline. Groups were divided and , simultaneously to pumpsurgery, injected intracardiac with siRNA-TRH and siRNA-Con as its control.Body weight, water consume and SABP were measured daily.As expected, AII significantly increased SABP (p<0.05) in both groupstreated , although cardiac hypertrophy (heart weight/body weight) was onlyevident in the group with the cardiac TRH system undamaged, suggesting that thecardiac TRH system function as a necessary mediator of the AII-inducedhypertrophic effect.As hypothesized, we found an AII-induced increase of TRH (p<0.05) geneexpression (real-t PCR) confirmed by immunohystochemestry that was not observedin the group AII+siRNA-TRH demonstrating the specific siRNA treatmentefficiency.Furthermore, AII significantly increase (p<0.05) BNP (hypertrophic marker),III collagen and TGFB (fibrosis markers) expressions only in the group with AIIwith the cardiac TRH system intact. On the contrary, the group with AII and thecTRH system inhibited, shows genes expressions similar to the saline controlgroup. Similar fibrotic results were observed with NIH3T3 cell culture where wedemonstrated that AII induced TRH gene expression (p<0.05) and itsinhibition impedes AII-induced increase of TGFB and III/I collagens expressionstelling us about the role of the cTRH in the AII fibrosis effects. We confirmedthese results by immunofluorescence.Our results point out that the cardiac TRH is involved in the AII-inducedhypertrophic and fibrotic effects.