Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Cátedra de Fisiología, Buenos Aires, Argentina.
CONICET - Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Buenos Aires, Argentina.
J Mol Endocrinol. 2021 Mar;66(3):207-221. doi: 10.1530/JME-20-0314.
Recent studies have provided evidence that triiodothyronine (T3) might play an effective role in the recovery of ischemic myocardium, through the preservation of mitochondrial function and the improvement of energy substrate metabolism. To this respect, it has been suggested that T3 could activate AMP-activated protein kinase (AMPK), the cellular 'fuel-gauge' enzyme, although its role has yet to be elucidated. The aim of the present study was to investigate the effects produced by acute treatment with T3 (60 nM) and the pharmacological inhibition of AMPK by compound C on isolated rat left atria subjected to 75 min simulated ischemia-75 min reperfusion. Results showed that T3 increased AMPK activation during simulated ischemia-reperfusion, while compound C prevented it. At the end of simulated reperfusion, acute T3 treatment increased contractile function recovery and cellular viability conservation. Mitochondrial ultrastructure was better preserved in the presence of T3 as well as mitochondrial ATP production rate and tissue ATP content. Calcium retention capacity, a parameter widely used as an indicator of the resistance of mitochondrial permeability transition pore (MPTP) to opening, and GSK-3β phosphorylation, a master switch enzyme that limits MPTP opening, were increased by T3 administration. All these beneficial effects exerted by T3 acute treatment were prevented when compound C was co-administrated. The present study provided original evidence that T3 enhances intrinsic activation of AMPK during myocardial ischemia-reperfusion, being this enzyme involved, at least in part, in the protective effects exerted by T3, contributing to mitochondrial structure and function preservation, post-ischemic contractile recovery and conservation of cellular viability.
最近的研究提供了证据，表明三碘甲状腺原氨酸（T3）可能通过保护线粒体功能和改善能量底物代谢在缺血性心肌的恢复中发挥有效作用。在这方面，有人认为 T3 可以激活 AMP 激活的蛋白激酶（AMPK），即细胞的“燃料计”酶，尽管其作用尚待阐明。本研究的目的是研究急性 T3（60 nM）处理和化合物 C 对 AMPK 的药理学抑制对 75 分钟模拟缺血-75 分钟再灌注分离的大鼠左心房产生的影响。结果表明，T3 在模拟缺血-再灌注期间增加 AMPK 激活，而化合物 C 则阻止了这种激活。在模拟再灌注结束时，急性 T3 处理增加了收缩功能恢复和细胞活力的保存。T3 的存在还更好地保护了线粒体超微结构以及线粒体 ATP 产生率和组织 ATP 含量。钙保留能力是作为线粒体通透性转换孔（MPTP）开放阻力的广泛使用的指标，GSK-3β磷酸化是限制 MPTP 开放的主要开关酶，T3 给药增加了这些参数。当共同给予化合物 C 时，T3 急性处理产生的所有这些有益作用都被阻止。本研究提供了原始证据，表明 T3 在心肌缺血再灌注期间增强 AMPK 的内在激活，该酶至少部分参与了 T3 发挥的保护作用，有助于线粒体结构和功能的保存、缺血后收缩功能的恢复和细胞活力的保存。
