title: 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.affiliation: Institute of Clinical Physiology, CNR, Pisa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Forini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lionetti
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
authors.forename: Angela
authors.initials: A
authors.lastname: Pucci
authors.forename: Federica
authors.initials: F
authors.lastname: Cecchetti
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ghanefar
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Nicolini
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Monica
authors.initials: M
authors.lastname: Nannipieri
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Recchia
authors.forename: Giorgio
authors.initials: G
authors.lastname: Iervasi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002196:Capillaries / Q000187:drug effects / Q000503:physiopathology; D002478:Cells, Cultured; D006439:Hemodynamics / Q000187:drug effects; D020249:Hormone Replacement Therapy; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D055104:Infusions, Subcutaneous; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013974:Thyroxine / Q000097:blood; D013997:Time Factors; D014284:Triiodothyronine / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016877:Oxidants; D014284:Triiodothyronine; D006861:Hydrogen Peroxide; D013974:Thyroxine