Left Ventricle Overexpression of Cardiac Thyrotropin Releasing Hormone (TRH) Induces Hypertrophy Features in the Normal Heart.

SCHUMAN, MARIANO LUIS; PERES DIAZ, LUDMILA S; LANDA, MARIA SILVINA; TOBLLI, J; CAO, GABRIEL; ALVAREZ, AZUCENA LAURA; FINKIELMAN, SAMUEL; PIROLA, CARLOS JOSE; GARCIA , SILVIA INES

Orlando

Congreso; Council of High Blood Pressure, American Heart Association; 2011

American Heart Association

We described the involvement of cardiac TRH in LV (left ventricle) 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 a fall in BP (Schuman et al Hypertension,2011). It’s known that the SHR model includes other systems impairment (RAS, SNS, 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 PCVM (control) was injected 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, immunohistochemical analysis using an antibody against TRH and Sirius red staining to evaluate ECM expansion. As expected, there was a significantly(p 004) increase 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 a significantly (p 0.04) increase (% 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, our 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.