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: Mariano L Schuman, Ludmila S Peres Diaz, Maria S Landa, Jorge E Toblli, Gabriel Cao, Azucena L Alvarez, Samuel Finkielman, Carlos J Pirola, Silvia I García
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 307 Issue 11 Pg. H1667-74 (Dec 01 2014) ISSN: 1522-1539 [Electronic] United States
• PMID: 25281568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the American Physiological Society.

Chemical References

• DNA, Complementary
• Thyrotropin-Releasing Hormone

Topics

• Animals
• Animals, Newborn
• Blood Pressure (physiology)
• DNA, Complementary (biosynthesis, genetics)
• Fibroblasts (pathology)
• Fibrosis
• Heart Ventricles (pathology)
• Hypertrophy, Left Ventricular (etiology, pathology)
• Male
• Myocytes, Cardiac (pathology)
• Rats
• Rats, Inbred SHR
• Rats, Wistar
• Thyrotropin-Releasing Hormone (biosynthesis, genetics, physiology)
• Up-Regulation