Early long-term L-T3 replacement rescues mitochondria and prevents ischemic cardiac remodelling in rats
Open accessAbstract
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.
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T3 mitochondrial protection is also exerted through the mitochondrial ATP-dependent potassium pathway, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and mitochondrial transcription factor A.
“T 3 mitochondrial protection is also exerted through other pathways, including mitochondrial adenosine triphosphatedependent potassium pathway, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and the mitochondrial transcription factor A (25).”
From Thyroid Hormones and Cardiovascular Function and Diseases (2018) · cites this paper as [25]
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- Authors
- Forini, F., Lionetti, V., Ardehali, H., Pucci, A., Cecchetti, F., Ghanefar, M., Nicolini, G., Ichikawa, Y., Nannipieri, M., Recchia, F. A., & Iervasi, G.
- Affiliations
- Istituto di Fisiologia Clinica (IT)
- Scuola Superiore Sant'Anna (IT)
- Northwestern University (US)
- Azienda Ospedaliera Universitaria Pisana (IT)
- University of Pisa (IT)
- Corresponding author
- Iervasi, Giorgio
- ORCID
- Venue
- Journal of Cellular and Molecular Medicine
- Publisher
- Wiley
- Published
- 2010-01-20
- Volume
- 15
- Issue
- 3
- Pages
- 514-524
- ISSN
- 1582-1838 (ISSN-L)
- PMC
- PMC3922373
- OpenAlex
- W2013644808
- Cited by
- 98
- References
- 54
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 3 · 2020: 8 · 2019: 7 · 2018: 6 · 2017: 5 · 2016: 12 · 2015: 8 · 2014: 6 · 2013: 6 · 2012: 4
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cellular and Molecular Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutional Research Information System (Sant'Anna School of Advanced Studies) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL108213, R01HL087149, K08HL079387)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Keywords
- levothyroxine, triiodothyronine, myocardial infarction, mitochondrial biogenesis, mitochondrial transcription, hypoxia-inducible factor-1α, TFAM, PGC-1α, angiogenesis, cardiomyocyte survival, hydrogen peroxide-induced cell death, mitoKATP channel, heart failure prevention, left ventricular ejection fraction
- MeSH terms
- Animals, Capillaries, Cells, Cultured, Hemodynamics, Hydrogen Peroxide, Male, Mitochondria, Myocardial Infarction, Random Allocation, Thyroxine, Time Factors, Triiodothyronine, Blotting, Western, Oxidants, Rats, Wistar, Apoptosis, Reverse Transcriptase Polymerase Chain Reaction, Hormone Replacement Therapy, Ventricular Remodeling, Myocytes, Cardiac, Rats, Hypoxia-Inducible Factor 1, alpha Subunit, Infusions, Subcutaneous
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