title: Thyrotropin-releasing hormone overexpression induces structural changes of the left ventricle in the normal rat heart.
abstract: Thyrotropin-releasing hormone (TRH) hyperactivity has been observed in the left ventricle of spontaneously hypertensive rats. Its long-term inhibition suppresses the development of hypertrophy, specifically preventing fibrosis. The presence of diverse systemic abnormalities in spontaneously hypertensive rat hearts has raised the question of whether specific TRH overexpression might be capable of inducing structural changes in favor of the hypertrophic phenotype in normal rat hearts. We produced TRH overexpression in normal rats by injecting into their left ventricular wall a plasmid driving expression of the preproTRH gene (PCMV-TRH). TRH content and expression of preproTRH, collagen type III, brain natriuretic peptide, β-myosin heavy chain, Bax-to-Bcl-2 ratio, and caspase-3 were measured. The overexpression maneuver was a success, as we found a significant increase in both tripeptide and preproTRH mRNA levels in the PCMV-TRH group compared with the control group. Immunohistochemical staining against TRH showed markedly positive brown signals only in the PCMV-TRH group. TRH overexpression induced a significant increase in fibrosis, evident in the increase of collagen type III expression accompanied by a significant increase in extracellular matrix expansion. We found a significant increase in brain natriuretic peptide and β-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 cultures (fibroblasts and myocytes). In conclusion, these results show that a specific TRH increase in the left ventricle induced structural changes in the normal heart, thus making the cardiac TRH system a promising therapeutic target.
authors.affiliation: Laboratory of Molecular Cardiology, Institute of Medical Research "Alfredo Lanari," Buenos Aires University, Buenos Aires, Argentina;
authors.forename: Mariano L
authors.initials: ML
authors.lastname: Schuman
authors.affiliation: Laboratory of Molecular Cardiology, Institute of Medical Research "Alfredo Lanari," Buenos Aires University, Buenos Aires, Argentina;
authors.forename: Ludmila S
authors.initials: LS
authors.lastname: Peres Diaz
authors.affiliation: Laboratory of Molecular Cardiology, Institute of Medical Research "Alfredo Lanari," Buenos Aires University, Buenos Aires, Argentina; Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research Lanari, Buenos Aires University and Argentinian National Council of Research and Technology, Buenos Aires, Argentina; and.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Landa
authors.affiliation: Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Toblli
authors.affiliation: Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Cao
authors.affiliation: Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research Lanari, Buenos Aires University and Argentinian National Council of Research and Technology, Buenos Aires, Argentina; and.
authors.forename: Azucena L
authors.initials: AL
authors.lastname: Alvarez
authors.affiliation: Laboratory of Molecular Cardiology, Institute of Medical Research "Alfredo Lanari," Buenos Aires University, Buenos Aires, Argentina;
authors.forename: Samuel
authors.initials: S
authors.lastname: Finkielman
authors.affiliation: Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research Lanari, Buenos Aires University and Argentinian National Council of Research and Technology, Buenos Aires, Argentina; and.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Pirola
authors.affiliation: Laboratory of Molecular Cardiology, Institute of Medical Research "Alfredo Lanari," Buenos Aires University, Buenos Aires, Argentina; garcia.silvia@lanari.fmed.uba.ar.
authors.forename: Silvia I
authors.initials: SI
authors.lastname: García
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000502:physiology; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D006352:Heart Ventricles / Q000473:pathology*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology; D008297:Male; D032383:Myocytes, Cardiac / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013973:Thyrotropin-Releasing Hormone / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D018076:DNA, Complementary; D013973:Thyrotropin-Releasing Hormone
keywords: fibrosis; heart; rat; thyrotropin-releasing hormone