Thyrotropin-Releasing Hormone Overexpression induces structural changes of the Left Ventricle in the normal Rat heart.

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

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY

AMER PHYSIOLOGICAL SOC

Lugar: Bethesda; Año: 2014 vol. 307 p. 1667 - 1674

0363-6135

Thyrotropin-releasing hormone (TRH) hyperactivity was observed in left ventricle of spontaneously hypertensive rats (SHR). Its long-term inhibition suppresses the development of hypertrophy, specifically preventing fibrosis. The presence of diverse systemic abnormalities in the SHR have raised the question of whether specific TRH overexpression might be capable of inducing structural changes in favor of the hypertrophic phenotype in a normal rat heart. We produce a TRH overexpression in normal rats by injecting into their left ventricular wall a plasmid driving the expression of the preproTRH gene (PCMV-TRH). TRH content and expression of preproTRH, collagen III, brain natriuretic peptide, beta-myosin heavy chain, Bax/Bcl2 ratio and caspase-3 were measured. Overexpression manoeuvre was a success, as we found a significant increase in both tripeptide and preproTRH mRNA levels in the PCMV-TRH compared to the control group. Immunohistochemical staining against TRH showed markedly positive brown signal only in the PCMV-TRH group. TRH overexpression induced a significant increase in fibrosis, evident in the increased of collagen III expression accompanied by a significant increase in extracellular matrix expansion. We found a significant increase in brain natriuretic peptide and beta-myosin heavy chain expression (recognized markers of hypertrophy). Moreover, TRH overexpression induced a slight but significant increase in myocyte diameter, indicating the onset of cell hypertrophy. We confirmed the data "in vitro" using primary cardiac cell culture (fibroblasts and myocytes). Conclusion: These results showed that a specific TRH increase in left ventricle induced structural changes in the normal heart, thus making the cardiac TRH system a promising therapeutic target.