Institute of Clinical Physiology, CNR, Pisa, Italy.
J Cell Mol Med. 2011 Mar;15(3):514-24. doi: 10.1111/j.1582-4934.2010.01014.x.
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.
3,5,3'-左旋甲状腺素（L-T3）对 DNA 转录、线粒体生物发生和呼吸至关重要，但在心肌梗死（MI）后其循环水平迅速下降。我们的主要研究目的是检测 MI 后早期和持续的 L-T3 血清水平正常化是否通过线粒体保护发挥心肌保护作用。在前降支结扎诱导 MI 后 72 小时，通过 4 周的时间向大鼠输注合成 L-T3（1.2μg/kg/天）或盐水。与盐水相比，L-T3 输注使 FT3 血清水平恢复到甲状腺功能正常状态（3.0±0.2 对 4.2±0.3pg/ml），改善左心室（LV）射血分数（39.5±2.5 对 65.5±6.9%），保留梗死周边区 LV 收缩末期壁增厚（6.34±3.1 对 33.7±6.21%），并使 LV 梗死瘢痕大小减少约 50%（均 P<0.05）。此外，L-T3 显著增加了血管生成和细胞存活，并增强了参与这些过程的核编码转录因子的表达。最后，L-T3 显著增加了 LV 梗死周边区线粒体 DNA 转录和生物发生相关因子的表达，如缺氧诱导因子-1α、线粒体转录因子 A 和过氧化物酶体增殖物激活受体 γ 共激活因子-1α。为了进一步探讨 L-T3 保护作用的机制，我们将分离的新生大鼠心肌细胞暴露于 H2O2 中，发现 L-T3 通过依赖于 mitoKATP 的途径挽救了线粒体生物发生和功能，并保护细胞免于死亡。MI 后早期和持续的循环 L-T3 水平的生理恢复使梗死瘢痕大小减半，并防止向心力衰竭的进展。这种有益作用可能是由于增强了毛细血管形成和线粒体保护。
