Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstr. 55, 45122, Essen, Germany.
Basic Res Cardiol. 2021 Apr 19;116(1):27. doi: 10.1007/s00395-021-00868-6.
Ischemic post-conditioning (iPoCo) by coronary re-occlusion/reperfusion during immediate reperfusion after prolonged myocardial ischemia reduces infarct size. Mechanical manipulation of culprit lesions, however, carries the risk of coronary microembolization which may obscure iPoCo's cardioprotection. Pharmacological post-conditioning with exogenous triiodothyronine (T3) could serve as an alternative conditioning strategy. Similar to iPoCo, T3 may activate cardioprotective prosurvival pathways. We aimed to study T3's impact on infarct size and its underlying signal transduction. Hearts were isolated from male Lewis rats (200-380 g), buffer-perfused and subjected to 30 min/120 min global zero-flow ischemia/reperfusion (I/R). In additional hearts, either iPoCo (2 × 30 s/30 s I/R) was performed or T3 (100-500 µg/L) infused at reperfusion. Infarct size was demarcated with triphenyl tetrazolium chloride staining and calculated as percent of ventricular mass. Infarct size was reduced with iPoCo to 16 ± 7% vs. 36 ± 4% with I/R only. The maximum infarct size reduction was observed with 300 µg/L T3 (14 ± 2%). T3 increased the phosphorylation of protein kinase B and mitogen extracellular-regulated-kinase 1/2, both key enzymes of the reperfusion injury salvage kinase (RISK) pathway. Pharmacological RISK blockade (RISK-BL) during reperfusion abrogated T3's cardioprotection (35 ± 10%). Adult ventricular cardiomyocytes were isolated from buffer-perfused rat hearts and exposed to 30 min/5 min hypoxia/reoxygenation (H/R); reoxygenation was initiated without or with T3, respectively, and without or with RISK-BL, respectively. Maximal preservation of viability was observed with 500 µg/L T3 after H/R (27 ± 4% of all cells vs. 5 ± 3% in time-matched controls). Again, RISK-BL abrogated protection (11 ± 3%). Mitochondria were isolated at early reperfusion from buffer-perfused rat hearts without or with iPoCo or 300 µg/L T3, respectively, at reperfusion. T3 improved mitochondrial function (i.e.: increased respiration, adenosine triphosphate production, calcium retention capacity, and decreased reactive oxygen species formation) to a similar extent as iPoCo. T3 at reperfusion reduces infarct size by activation of the RISK pathway. T3's protection is a cardiomyocyte phenomenon and targets mitochondria.
缺血后处理（iPoCo）通过在长时间心肌缺血后立即再灌注时对罪犯病变进行再闭塞/再灌注，可减少梗死面积。然而，对罪犯病变进行机械操作会带来冠状动脉微栓塞的风险，从而掩盖 iPoCo 的心脏保护作用。外源性三碘甲状腺原氨酸（T3）的药物后处理可能是一种替代的预处理策略。与 iPoCo 类似，T3 可能激活心脏保护生存途径。我们旨在研究 T3 对梗死面积的影响及其潜在的信号转导。从雄性 Lewis 大鼠（200-380 克）中分离心脏，缓冲液灌注，并进行 30 分钟/120 分钟的全零流量缺血/再灌注（I/R）。在其他心脏中，进行 iPoCo（2×30 s/30 s I/R）或在再灌注时输注 T3（100-500 µg/L）。用三苯基四唑氯化物染色标记梗死面积，并计算为心室质量的百分比。iPoCo 将梗死面积减少到 16±7%，而仅 I/R 组为 36±4%。用 300 µg/L T3 观察到最大的梗死面积减少（14±2%）。T3 增加了蛋白激酶 B 和丝裂原活化蛋白激酶 1/2 的磷酸化，这两种都是再灌注损伤挽救激酶（RISK）途径的关键酶。在再灌注期间进行药物 RISK 阻断（RISK-BL）会消除 T3 的心脏保护作用（35±10%）。从缓冲液灌注的大鼠心脏中分离成年心室肌细胞，并暴露于 30 分钟/5 分钟缺氧/复氧（H/R）；复氧分别在没有或有 T3 的情况下开始，并且没有或有 RISK-BL。H/R 后观察到 500 µg/L T3 对活力的最大保护作用（与时间匹配的对照组相比，所有细胞的 27±4%，而 5±3%）。同样，RISK-BL 消除了保护作用（11±3%）。在再灌注时，从缓冲液灌注的大鼠心脏中没有或有 iPoCo 或 300 µg/L T3 分别分离线粒体。T3 改善了线粒体功能（即：增加呼吸、三磷酸腺苷产生、钙保留能力和减少活性氧物质的形成），与 iPoCo 相似。在再灌注时使用 T3 通过激活 RISK 途径减少梗死面积。T3 的保护作用是通过激活 RISK 途径实现的。T3 的保护作用是心肌细胞现象，针对线粒体。
