AdipoRon 减轻炎症和与心肺旁路诱导的全身炎症反应综合征相关的心脏功能受损,Journal of the American Heart Association

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AdipoRon 减轻炎症和与心肺旁路诱导的全身炎症反应综合征相关的心脏功能受损
Journal of the American Heart Association ( IF 5.0 ) Pub Date : 2021-03-05 , DOI: 10.1161/jaha.120.018097
Alexander Jenke _{1,

2} , Mariam Yazdanyar _{1,

2} , Shunsuke Miyahara _{1,

2} , Agunda Chekhoeva _{1,

2} , Moritz Benjamin Immohr _{1,

2} , Julia Kistner _{1,

2} , Udo Boeken _{1,

2} , Artur Lichtenberg _{1,

2} , Payam Akhyari _{1,

2}

Affiliation

背景使用体外循环 (CPB) 的心脏手术经常引发全身炎症反应综合征，这是由 TLR4（Toll 样受体 4）和 TNF-α（肿瘤坏死因子α）信号触发的。在这里，我们研究了脂联素受体 1 和 2 激动剂 AdipoRon 是否调节 CPB 诱导的炎症和心功能不全。与载体相比，AdipoRon 应用减轻了 CPB 引起的深度低温停循环后平均动脉压的损害。在断奶和断奶后阶段，所有 AdipoRon 动物（7 只中的 7 只）的心率和平均动脉压保持稳定，而在接受载体治疗的 7 只动物中，有 2 只的心律无法挽回地丧失。AdipoRon 介导的心脏循环参数的改善伴随着血浆 IL（白介素）10 水平的增加和乳酸和 K 浓度的降低⁺. 在心肌组织中，AdipoRon 激活 AMP 活化蛋白激酶 (AMPK)，同时减弱 CPB 诱导的核因子 κB 抑制剂 α (IκBα) 的降解，上调 TNF-α、IL-1β、CCL2（C-C 趋化因子配体 2），烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶和诱导型一氧化氮合酶。相应地，在培养的心肌细胞、心脏成纤维细胞和血管内皮细胞中，AdipoRon 激活 AMPK，上调 IL-10，并减弱核因子 κB 的激活，以及上调 TNF-α、IL-1β、CCL2、NADPH 氧化酶，脂多糖或TNF-α诱导的诱导型一氧化氮合酶。此外，

"点击查看英文标题和摘要"

AdipoRon Attenuates Inflammation and Impairment of Cardiac Function Associated With Cardiopulmonary Bypass–Induced Systemic Inflammatory Response Syndrome

BackgroundCardiac surgery using cardiopulmonary bypass (CPB) frequently provokes a systemic inflammatory response syndrome, which is triggered by TLR4 (Toll‐like receptor 4) and TNF‐α (tumor necrosis factor α) signaling. Here, we investigated whether the adiponectin receptor 1 and 2 agonist AdipoRon modulates CPB‐induced inflammation and cardiac dysfunction.Methods and ResultsRats underwent CPB with deep hypothermic circulatory arrest and were finally weaned from the heart‐lung machine. Compared with vehicle, AdipoRon application attenuated the CPB‐induced impairment of mean arterial pressure following deep hypothermic circulatory arrest. During the weaning and postweaning phases, heart rate and mean arterial pressure in all AdipoRon animals (7 of 7) remained stable, while cardiac rhythm was irretrievably lost in 2 of 7 of the vehicle‐treated animals. The AdipoRon‐mediated improvements of cardiocirculatory parameters were accompanied by increased plasma levels of IL (interleukin) 10 and diminished concentrations of lactate and K⁺. In myocardial tissue, AdipoRon activated AMP‐activated protein kinase (AMPK) while attenuating CPB‐induced degradation of nuclear factor κB inhibitor α (IκBα), upregulation of TNF‐α, IL‐1β, CCL2 (C‐C chemokine ligand 2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and inducible nitric oxide synthase. Correspondingly, in cultured cardiac myocytes, cardiac fibroblasts, and vascular endothelial cells, AdipoRon activated AMPK, upregulated IL‐10, and attenuated activation of nuclear factor κB, as well as upregulation of TNF‐α, IL‐1β, CCL2, NADPH oxidase, and inducible nitric oxide synthase induced by lipopolysaccharide or TNF‐α. In addition, the treatment of cardiac myocytes with the AMPK activator 5‐aminoimidazole‐4‐carboxamide 1‐β‐D‐ribofuranoside resulted in a similar inhibition of lipopolysaccharide‐ and TNF‐α–induced inflammatory cell phenotypes as for AdipoRon.ConclusionsOur observations indicate that AdipoRon attenuates CPB‐induced inflammation and impairment of cardiac function through AMPK‐mediated inhibition of proinflammatory TLR4 and TNF‐α signaling in cardiac cells and upregulation of immunosuppressive IL‐10.

更新日期：2021-03-16

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