Early long-term L-T3 replacement rescues mitochondria and prevents ischemic cardiac remodelling in rats.

Abstract

3,5,3'-Levo-triiodothyronine (L-T3) is essential for DNA transcription, mitochondrial biogenesis and respiration, but its circulating levels rapidly decrease after myocardial infarction (MI). The main aim of our study was to test whether an early and sustained normalization of L-T3 serum levels after MI exerts myocardial protective effects through a mitochondrial preservation. Seventy-two hours after MI induced by anterior interventricular artery ligation, rats were infused with synthetic L-T3 (1.2 μg/kg/day) or saline over 4 weeks. Compared to saline, L-T3 infusion restored FT3 serum levels at euthyroid state (3.0 ± 0.2 versus 4.2 ± 0.3 pg/ml), improved left ventricular (LV) ejection fraction (39.5 ± 2.5 versus 65.5 ± 6.9%), preserved LV end-systolic wall thickening in the peri-infarct zone (6.34 ± 3.1 versus 33.7 ± 6.21%) and reduced LV infarct-scar size by approximately 50% (all P < 0.05). Moreover, L-T3 significantly increased angiogenesis and cell survival and enhanced the expression of nuclear-encoded transcription factors involved in these processes. Finally, L-T3 significantly increased the expression of factors involved in mitochondrial DNA transcription and biogenesis, such as hypoxic inducible factor-1α, mitochondrial transcription factor A and peroxisome proliferator activated receptor γ coactivator-1α, in the LV peri-infarct zone. To further explore mechanisms of L-T3 protective effects, we exposed isolated neonatal cardiomyocytes to H(2)O(2) and found that L-T3 rescued mitochondrial biogenesis and function and protected against cell death via a mitoKATP dependent pathway. Early and sustained physiological restoration of circulating L-T3 levels after MI halves infarct scar size and prevents the progression towards heart failure. This beneficial effect is likely due to enhanced capillary formation and mitochondrial protection.

• Authors: Francesca Forini, Vincenzo Lionetti, Hossein Ardehali, Angela Pucci, Federica Cecchetti, Mohsen Ghanefar, Giuseppina Nicolini, Yoshihiko Ichikawa, Monica Nannipieri, Fabio A Recchia, Giorgio Iervasi
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 15 Issue 3 Pg. 514-24 (Mar 2011) ISSN: 1582-4934 [Electronic] England
• PMID: 20100314 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Chemical References

• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• Oxidants
• Triiodothyronine
• Hydrogen Peroxide
• Thyroxine

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Capillaries (drug effects, physiopathology)
• Cells, Cultured
• Hemodynamics (drug effects)
• Hormone Replacement Therapy
• Hydrogen Peroxide (pharmacology)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Infusions, Subcutaneous
• Male
• Mitochondria (drug effects, genetics, metabolism)
• Myocardial Infarction (physiopathology, prevention & control)
• Myocytes, Cardiac (cytology, drug effects, metabolism)
• Oxidants (pharmacology)
• Random Allocation
• Rats
• Rats, Wistar
• Reverse Transcriptase Polymerase Chain Reaction
• Thyroxine (blood)
• Time Factors
• Triiodothyronine (administration & dosage, blood, therapeutic use)
• Ventricular Remodeling (drug effects)