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. 2011 Mar;15(3):514-24.
doi: 10.1111/j.1582-4934.2010.01014.x.

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

Francesca Forini  1 , Vincenzo Lionetti, Hossein Ardehali, Angela Pucci, Federica Cecchetti, Mohsen Ghanefar, Giuseppina Nicolini, Yoshihiko Ichikawa, Monica Nannipieri, Fabio A Recchia, Giorgio Iervasi
Affiliations

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

Francesca Forini et al. J Cell Mol Med. 2011 Mar.

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.

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Figures

Fig 1
Fig 1
Global (A–C) and regional (D–F) LV function. (G) Representative LV M-Mode echocardiograms for each experimental condition. MI: myocardial infarction; LVEF: LV ejection fraction; LVFS: LV fractional shortening; LVD: LV diameters; LVTBZ: LV thickness of the border zone; LVTRZ: LV thickness of the remote zone; ED: end diastolic; ES: end systolic; LVESTHK: LV end-systolic wall thickening; BZ: border zone; RZ: remote zone; LVEDV: LV end-diastolic volume; LVESV: LV end-systolic volume; ED: end-diastolic; ES: end-systolic. Values are means ± S.E.M.; n= 8 animals per group. *P < 0.05 versus Sham; #P < 0.05 versus 72 hrs MI; †P < 0.05 versus T3–.
Fig 2
Fig 2
(A) Representative LV transverse slice cut at midseptal level from T3+ treated rats showed a significant reduced infarct-scar size compared with T3– animals (magnification, 10); (B) LV collagen accumulation revealed by Masson trichrome staining (magnification, 40). Values are means ± S.E.M.; n= 8 animals per group. *P < 0.05 versus T3–.
Fig 3
Fig 3
(A) Immunohistochemical detection of endothelial cells identified by CD31 (black arrows) in border (BZ) and remote zone (RZ) of infarcted hearts to quantify LV capillary density (magnification, 400). (B) Western blot analysis of THR-β normalized to β-actin in BZ and RZ of infarcted hearts. Values are means ± S.E.M. (n= 6 microscopic fields per LV section); n= 8 animals per group. #P < 0.05 versus T3–; †P < 0.05 versus RZ.
Fig 4
Fig 4
TUNEL staining to quantify apoptotic cardiomyocytes (black arrows) in T3+ and T3− infarcted left ventricle and haematoxylin counterstaining (magnification, 400). Values are means ± S.E.M. (n= 6 microscopic fields per LV section); n= 8 animals per group. #P < 0.05 versus T3–; †P < 0.05 versus RZ.
Fig 5
Fig 5
Gene (A) and protein (B) expression of HIF-1α normalized to β-actin gene and protein expression in border (BZ) and remote zone (RZ) of infarcted hearts. Values are means ± S.E.M.; n= 8 animals per group. *P < 0.05 versus Sham; #P < 0.05 versus RZ; †P < 0.05 versus T3+.
Fig 6
Fig 6
Gene (A) and protein (B) expression of Mt-TFA and (C) gene expression of PGC-1α normalized to β-actin gene and protein expression in border (BZ) and remote zone (RZ) of infarcted hearts; (D) activity of the mitochondrial CcO-1 normalized to CS activity in BZ and RZ zone of infarcted hearts. Values are means ± S.E.M.; n= 8 animals per group. *P < 0.05 versus Sham; #P < 0.05 versus RZ; †P < 0.05 versus T3+.
Fig 7
Fig 7
In vitro studies in H2O2 stressed NRCM cultured for 48 hrs in presence or absence of L-T3: (A) TMRE uptake, (B) Trypan blue exclusion test, (C) activity of the mitochondrial CcO-1 normalized to CS activity and (D) relative mtDNA copy number. 5HD, 5- hydroxydecanoate. *P < 0.05 versus Control; #P < 0.05 versus H2O2; †P < 0.05 versus T3+ H2O2. Values are means ± S.E.M.; n= 3.
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