Age-Independent Cardiac Protection by Pharmacological Activation of Beclin-1 During Endotoxemia and Its Association With Energy Metabolic Reprograming in Myocardium-A Targeted Metabolomics Study.
Age-Independent Cardiac Protection by Pharmacological Activation of Beclin-1 During Endotoxemia and Its Association With Energy Metabolic Reprograming in Myocardium-A Targeted Metabolomics Study.
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DOI：
10.1161/jaha.122.025310
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发表时间：
2022-07-19
影响因子：
5.4
通讯作者：
Zang, Qun Sophia
中科院分区：
文献类型：
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作者：
Kim, Matthew;Nikouee, Azadeh;Zou, Raymond;Ren, Di;He, Zhibin;Li, Ji;Wang, Lu;Djukovic, Danijel;Raftery, Daniel;Purcell, Hayley;Promislow, Daniel;Sun, Yuxiao;Goodarzi, Mohammad;Zhang, Qing-Jun;Liu, Zhi-Ping;Zang, Qun Sophia
我们发现Beclin-1依赖性自噬可以保护经历内毒素血症的年轻和成年小鼠的心脏。在此，我们比较了Beclin-1激活肽TB-肽对年轻成年和老年小鼠内毒素血症诱导的心脏结局的潜在治疗作用。我们进一步评估了脂多糖（脂多糖）诱导的和TB肽治疗介导的心肌代谢改变。用脂多糖攻击10周龄和24月龄的C57 BL/6 J小鼠，使用发生心功能障碍的剂量。在TB肽或对照媒介物处理后，评价心脏收缩性、循环细胞因子和心肌自噬。我们检测到TB肽在内毒素血症期间促进了年轻和老年小鼠的自噬、减弱了细胞因子并改善了心脏性能。靶向代谢组学试验旨在检测361种已知代谢物，其中156种在至少1种心脏组织样本中检出。在所有年龄段的小鼠中发现了脂多糖诱导的葡萄糖和氨基酸代谢障碍，TB肽改善了这些改变。然而，脂多糖在年轻组中上调脂质代谢产物，但在老年组中中度下调，表明年龄依赖性反应。TB肽减轻了脂多糖介导的年轻小鼠的脂质趋势，但对老年小鼠几乎没有影响。（研究注册：项目DOI：https：//doi.org/10.21228/M8K11W）。TB-肽对Beclin-1的药理学激活在年轻和老年人群中的内毒素血症期间具有心脏保护作用，表明对脓毒症诱导的心肌病具有治疗潜力。代谢组学分析表明，TB肽的非年龄依赖性保护作用与通过葡萄糖和氨基酸代谢重新编程能量产生有关。
We showed that Beclin‐1‐dependent autophagy protects the heart in young and adult mice that underwent endotoxemia. Herein, we compared the potential therapeutic effects of Beclin‐1 activating peptide, TB‐peptide, on endotoxemia‐induced cardiac outcomes in young adult and aged mice. We further evaluated lipopolysaccharide (lipopolysaccharide)‐induced and TB‐peptide treatment‐mediated alterations in myocardial metabolism. C57BL/6J mice that were 10 weeks and 24 months old were challenged by lipopolysaccharide using doses at which cardiac dysfunction occurred. Following the treatment of TB‐peptide or control vehicle, heart contractility, circulating cytokines, and myocardial autophagy were evaluated. We detected that TB‐peptide boosted autophagy, attenuated cytokines, and improved cardiac performance in both young and aged mice during endotoxemia. A targeted metabolomics assay was designed to detect a pool of 361 known metabolites, of which 156 were detected in at least 1 of the heart tissue samples. Lipopolysaccharide‐induced impairments were found in glucose and amino acid metabolisms in mice of all ages, and TB‐peptide ameliorated these alterations. However, lipid metabolites were upregulated in the young group but moderately downregulated in the aged by lipopolysaccharide, suggesting an age‐dependent response. TB‐peptide mitigated lipopolysaccharide‐mediated trend of lipids in the young mice but had little effect on the aged. (Study registration: Project DOI: https://doi.org/10.21228/M8K11W). Pharmacological activation of Beclin‐1 by TB‐peptide is cardiac protective in both young and aged population during endotoxemia, suggest a therapeutic potential for sepsis‐induced cardiomyopathy. Metabolomics analysis suggests that an age‐independent protection by TB‐peptide is associated with reprograming of energy production via glucose and amino acid metabolisms.