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

Francesca Forini, Vincenzo Lionetti, Hossein Ardehali, Angela Pucci, Federica Cecchetti, Mohsen Ghanefar, Giuseppina Nicolini, Yoshihiko Ichikawa, Monica Nannipieri, Fabio A. Recchia, Giorgio Iervasi*

*Corresponding author for this work

Research output: Contribution to journalArticle

58 Scopus citations

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 H2O2 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.

Original languageEnglish (US)
Pages (from-to)514-524
Number of pages11
JournalJournal of Cellular and Molecular Medicine
Volume15
Issue number3
DOIs
StatePublished - Mar 2011

Keywords

  • Angiogenesis
  • L-triiodothyronine
  • MitoKATP
  • Myocardial infarction
  • Remodelling

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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    Forini, F., Lionetti, V., Ardehali, H., Pucci, A., Cecchetti, F., Ghanefar, M., Nicolini, G., Ichikawa, Y., Nannipieri, M., Recchia, F. A., & Iervasi, G. (2011). Early long-term L-T3 replacement rescues mitochondria and prevents ischemic cardiac remodelling in rats. Journal of Cellular and Molecular Medicine, 15(3), 514-524. https://doi.org/10.1111/j.1582-4934.2010.01014.x