THYROTROPIN RELEASING HORMONE (TRH) OVEREXPRESSION INDUCES LEFT VENTRICLE HYPERTROPHY FEATURES IN THE NORMAL HEART.

MARIANO L. SCHUMAN; LUDMILA S PERES DIAZ; MARÍA S. LANDA; JORGE E TOBLLI; GABRIEL CAO; AZUCENA L. ALVAREZ; SAMUEL FINKIELMAN; CARLOS J. PIROLA; SILVIA I GARCÍA

Orlando Fl

Congreso; High Blood Pressure Research 2011; 2011

American Heart Association

We described the involvement of cardiac TRH in LV hypertrophy of SHR. SHR presents a LV-TRH hyperactivity, consequently the LV-TRH long-term inhibition by interference RNA avoid the development of hypertrophy as it prevented LV fibrosis, cardiomyocite enlargement and attenuate the expression of BNP, even in the absence of  fall in BP (Schuman et al Hypertension,2011).It’s known that the SHR model includes other systems impairment (RAS, etc) and these observations raised the question if a specific LV-TRH overexpression would be capable to induce the hypertrophy phenotype in a normal rat?For TRH overexpression an eucariotic plasmid PCMV-TRH or PCMV (cont) was injected directly into LV wall weekly during 4 weeks. Hypertrophy was expressed as HW/BW. TRH (RIA), preproTRH, BNP, collagen, ß-MCH, bax, bcl2,caspase,IL6 and angiotensinogen expressions real time rt-PCR) were measured. Hearts were processed for morphometric studies and immunohistochemical analysis using anti-TRH and Sirius red staining to evaluate ECM expansion.As expected, there was an increase (p<0.04) of both tripeptide (0.16 +0.05 vs 0.30+0.04 pgTRH/mg protein) and pre-proTRH mRNA (325% vs 100%) levels in wistar injected with PCMV-TRH vs control. In accordance, immunohistochemical analysis using an antibody against TRH showed a significantly and markedly brown stain in the PCMV-TRH group. Specific LV-TRH overexpression induced an increase (p<0.04) (% vs control group) in BNP (a recognized marker of hypertrophy, 222%), III collagen 257%) and ß-MHC expression (261%). Accordingly, the evaluation of ECM stain showed a significantly (p<0.03) increase in ECM expansion.Moreover, LV-overexpression induces a significant increase in myocyte diameter vs control group (26.3+2.3 vs 23.8+ 2.1 μm, p<0.04) and consequently reduces number of capillaries /area ( 25.6+1.8 vs 28.1+ 2.0 p<0.05) indicating hypertrophy development in these animals.Although LV-TRH overexpression induces hypertrophy features, we observed a normal HW/BW ratio probably due to the shortness of the treatment (4 weeks).In conclusion, results demonstrated that the only increase of LV-TRH induces hypertrophy features in a normal heart and raise the hopes that cardiac TRH system may be a new target in LV hypertrophy.