The AMPK Activator Aicar Ameliorates Age-Dependent Myocardial Injury in Murine Hemorrhagic Shock.
The AMPK Activator Aicar Ameliorates Age-Dependent Myocardial Injury in Murine Hemorrhagic Shock.
复制标题
DOI：
10.1097/shk.0000000000000730
复制
发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Zingarelli B
中科院分区：
文献类型：
--
作者：
Matsiukevich D;Piraino G;Klingbeil LR;Hake PW;Wolfe V;O'Connor M;Zingarelli B
失血性休克患者心肌功能不全的发生受患者年龄的显著影响。AMP活化蛋白激酶（AMPK）是能量稳态的关键协调者，在细胞应激后协调代谢恢复。我们研究了AMPK调节的途径是否是年龄依赖性的，以及5-氨基-4-咪唑甲酰胺核苷（AICAR）激活AMPK是否具有心脏保护作用。麻醉的C57/BL 6年轻（3-5月龄）和成熟雄性小鼠（9-12月龄）通过抽血进行失血性休克，然后用流出的血和乳酸林格氏溶液复苏。在复苏后3小时处死小鼠，收获血浆和心脏用于生化测定。与年轻小鼠相比，溶剂处理的成熟小鼠表现出更高的心肌损伤和更高水平的心血管损伤的血浆生物标志物（内皮素和卵泡抑素）。与年轻小鼠相比，溶剂处理的成熟小鼠的心脏细胞线粒体结构也明显受损。在分子分析中，磷酸化催化亚基pAMPKα的增加与年轻小鼠中过氧化物酶体增殖物激活受体γ共激活因子-α的核转位相关，但与成熟小鼠无关。通过轻链（LC）3B-I蛋白转化为LC 3B-II形式评价，未观察到自噬的变化。AICAR治疗改善了两个年龄组的心肌损伤。然而，AICAR治疗效果在成熟小鼠中的效果不如年轻小鼠，并且涉及不同的作用机制。因此，我们的数据表明，在失血性休克AMPK依赖的代谢机制是重要的，以减轻心肌损伤。然而，随着年龄的增长，这些机制的能力下降。
The development of myocardial dysfunction in patients with hemorrhagic shock is significantly impacted by the patient age. AMP-activated protein kinase (AMPK) is a pivotal orchestrator of energy homeostasis, which coordinates metabolic recovery after cellular stress. We investigated whether AMPK-regulated pathways are age-dependent in hemorrhage-induced myocardial injury and whether AMPK activation by 5-amino-4-imidazole carboxamide riboside (AICAR) affords cardioprotective effects. Anesthetized C57/BL6 young (3–5 months old) and mature male mice (9–12 months old) were subjected to hemorrhagic shock by blood withdrawing followed by resuscitation with shed blood and Lactated Ringer’s solution. Mice were sacrificed at 3 hours after resuscitation, and plasma and hearts were harvested for biochemical assays. Vehicle-treated mature mice exhibited higher myocardial injury and higher levels of plasma biomarkers of cardiovascular injury (endocan and follistatin) when compared with young mice. Cardiac cell mitochondrial structure was also markedly impaired in vehicle-treated mature mice when compared to young mice. At molecular analysis, an increase of the phosphorylated catalytic subunit pAMPKα was associated with nuclear translocation of the peroxisome proliferator-activated receptor γ co-activator-α in young, but not mature mice. No changes in autophagy were observed as evaluated by the conversion of the light-chain (LC)3B-I protein to LC3B-II form. Treatment with AICAR ameliorated myocardial damage in both age groups. However, AICAR therapeutic effects were less effective in mature mice compared to young mice and involved distinct mechanisms of action. Thus, our data demonstrate that during hemorrhagic shock AMPK-dependent metabolic mechanisms are important for mitigating myocardial injury. However, these mechanisms are less competent with age.