Cardiac Thyrotropin-releasing Hormone Inhibition Improves Ventricular Function and Reduces Hypertrophy and Fibrosis After Myocardial Infarction in Rats |
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| Authors: | Mariano L Schuman Ludmila S Peres Diaz Maia Aisicovich Fernando Ingallina Jorge E Toblli Maria S Landa Silvia I García |
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| Institution: | 1. University of Buenos Aires, School of Medicine, Institute of Medical Research A. Lanari, Ciudad Autónoma de Buenos Aires, Argentina;2. National Scientific and Technical Research Council (CONICET), University of Buenos Aires (UBA), Institute of Medical Research (IDIM), Department of Molecular Cardiology, Ciudad Autónoma de Buenos Aires, Argentina;3. National Scientific and Technical Research Council (CONICET), University of Buenos Aires (UBA), Institute of Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, Ciudad Autonoma de Buenos Aires, Argentina;4. Laboratory of Experimental Medicine, Hospital Alemán, Ciudad Autonoma de Buenos Aires, Argentina;5. University of Buenos Aires (UBA), School of Medicine, Institute of Medical Research “Alfredo Lanari,” Department of Cardiology, Ciudad Autonoma de Buenos Aires, Argentina;1. University of Washington, Department of Medicine, Seattle, WA;2. Medical University of South Carolina, Department of Medicine, Charleston, SC;3. University of Wisconsin, Department of Radiology, Madison, WI;4. Perelman School of Medicine at the University of Pennsylvania, Departments of Medicine and Epidemiology, Philadelphia, PA;5. Johns Hopkins Hospital, Department of Medicine, Baltimore, MD;6. University of Washington, Department of Biostatistics, Seattle, WA;7. Johns Hopkins Hospital, Department of Radiology, Baltimore, MD;8. University of Washington, Department of Epidemiology, Seattle, WA;1. Department of Cardiology, Hartcentrum, Jessa Hospital, Hasselt, Belgium;2. Department of Cardiovascular Medicine, UZ Leuven, Leuven, Belgium;3. Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium;4. Centre for Cardiovascular Diseases, University Hospital Brussels, Brussels, Belgium;1. Serbian Academy of Sciences and Arts, Belgrade, Serbia;2. Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan;3. Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;4. Department of Cardiology, Clinical Center of Serbia, Belgrade, Serbia;5. Faculty of Medicine, University of Belgrade, Belgrade, Serbia;6. Cardiovascular Pathology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy;7. Winters Center for Heart Failure, Cardiovascular Research Institute, Baylor College of Medicine, Michael E. DeBakey VA Medical Center, Houston, Texas;8. Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida;9. Attikon University Hospital, Department of Cardiology, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece;10. Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan;11. Department of Cardiovascular Medicine, Kitasato University Kitasato Institute Hospital, Tokyo, Japan;12. Cardiopathology, Institute for Pathology, University Hospital, Tuebingen, Germany;13. Department of Cardiovascular Medicine, Charles University, Prague, Czech Republic;14. National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London, UK;15. Heart and Vascular Center, Brigham and Women''s Hospital and Harvard Medical School, Boston, Massachusetts;16. Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan;17. Department of Cardiology (CVK); and Berlin Institute of Health Center for Regenerative Therapies (BCRT); German Centre for Cardiovascular Research (DZHK) partner site Berlin; Charité Universitätsmedizin Berlin, Germany;18. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan;19. Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan;20. Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany;21. Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany;22. Berlin Institute of Health (BIH) and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Department of Cardiology, Campus Virchow Klinikum, Charite University, Berlin, Germany;23. Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy;24. Monash University, Australia, and University of Warwick, Coventry, UK;25. Cleveland Clinic, Cleveland Ohio |
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| Abstract: | BackgroundCardiac thyrotropin-releasing hormone (TRH) is a tripeptide with still unknown functions. We demonstrated that the left ventricle (LV) TRH system is hyperactivated in spontaneously hypertensive rats and its inhibition prevented cardiac hypertrophy and fibrosis. Therefore, we evaluated whether in vivo cardiac TRH inhibition could improve myocardial function and attenuate ventricular remodeling in a rat model of myocardial infarction (MI).Methods and ResultsIn Wistar rats, MI was induced by a permanent left anterior descending coronary artery ligation. A coronary injection of a specific small interfering RNA against TRH was applied simultaneously. The control group received a scrambled small interfering RNA. Cardiac remodeling variables were evaluated one week later. In MI rats, TRH inhibition decreased LV end-diastolic (1.049 ± 0.102 mL vs 1.339 ± 0.102 mL, P < .05), and end-systolic volumes (0.282 ± 0.043 mL vs 0.515 ± 0.037 mL, P < .001), and increased LV ejection fraction (71.89 ± 2.80% vs 65.69 ± 2.85%, P < .05). Although both MI groups presented similar infarct size, small interfering RNA against TRH treatment attenuated the cardiac hypertrophy index and myocardial interstitial collagen deposition in the peri-infarct myocardium. These effects were accompanied by attenuation in the rise of transforming growth factor-β, collagen I, and collagen III, as well as the fetal genes (atrial natriuretic peptide, B-type natriuretic peptide, and beta myosin heavy chain) expression in the peri-infarct region. In addition, the expression of Hif1α and vascular endothelial growth factor significantly increased compared with all groups.ConclusionsCardiac TRH inhibition improves LV systolic function and attenuates ventricular remodeling after MI. These novel findings support the idea that TRH inhibition may serve as a new therapeutic strategy against the progression of heart failure. |
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