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聚肌苷酸胞苷酸预处理通过 TLR3/PI3K/Akt 依赖性途径保护心脏免受心肌缺血/再灌注损伤。

Poly(I:C) preconditioning protects the heart against myocardial ischemia/reperfusion injury through TLR3/PI3K/Akt-dependent pathway.

机构信息

Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

出版信息

Signal Transduct Target Ther. 2020 Nov 6;5(1):216. doi: 10.1038/s41392-020-00257-w.

DOI:10.1038/s41392-020-00257-w
PMID:33154351
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7644758/
Abstract

Emerging evidence suggests that Toll-like receptors (TLRs) ligands pretreatment may play a vital role in the progress of myocardial ischemia/reperfusion (I/R) injury. As the ligand of TLR3, polyinosinic-polycytidylic acid (poly(I:C)), a synthetic double-stranded RNA, whether its preconditioning can exhibit a cardioprotective phenotype remains unknown. Here, we report the protective effect of poly(I:C) pretreatment in acute myocardial I/R injury by activating TLR3/PI3K/Akt signaling pathway. Poly(I:C) pretreatment leads to a significant reduction of infarct size, improvement of cardiac function, and downregulation of inflammatory cytokines and apoptotic molecules compared with controls. Subsequently, our data demonstrate that phosphorylation of TLR3 tyrosine residue and its interaction with PI3K is enhanced, and protein levels of phospho-PI3K and phospho-Akt are both increased after poly(I:C) pretreatment, while knock out of TLR3 suppresses the cardioprotection of poly(I:C) preconditioning through a decreased activation of PI3K/Akt signaling. Moreover, inhibition of p85 PI3K by the administration of LY294002 in vivo and knockdown of Akt by siRNA in vitro significantly abolish poly(I:C) preconditioning-induced cardioprotective effect. In conclusion, our results reveal that poly(I:C) preconditioning exhibits essential protection in myocardial I/R injury via its modulation of TLR3, and the downstream PI3K/Akt signaling, which may provide a potential pharmacologic target for perioperative cardioprotection.

摘要

新出现的证据表明，Toll 样受体（TLR）配体预处理可能在心肌缺血/再灌注（I/R）损伤的进展中发挥重要作用。作为 TLR3 的配体，聚肌苷酸-聚胞苷酸（poly(I:C)），一种合成的双链 RNA，其预处理是否能表现出心脏保护表型尚不清楚。在这里，我们通过激活 TLR3/PI3K/Akt 信号通路，报告了 poly(I:C)预处理在急性心肌 I/R 损伤中的保护作用。与对照组相比，poly(I:C)预处理可显著减少梗死面积，改善心功能，下调炎症细胞因子和凋亡分子。随后，我们的数据表明，TLR3 酪氨酸残基的磷酸化及其与 PI3K 的相互作用增强，poly(I:C)预处理后磷酸化 PI3K 和磷酸化 Akt 的蛋白水平均升高，而 TLR3 的敲除通过降低 PI3K/Akt 信号的激活抑制了 poly(I:C)预处理的心脏保护作用。此外，体内给予 LY294002 抑制 p85 PI3K 和体外使用 siRNA 敲低 Akt 均可显著消除 poly(I:C)预处理诱导的心脏保护作用。总之，我们的结果表明，poly(I:C)预处理通过调节 TLR3 及其下游的 PI3K/Akt 信号通路，在心肌 I/R 损伤中表现出重要的保护作用，这可能为围手术期心脏保护提供一个潜在的药物靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/feeb1c3e2973/41392_2020_257_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/13c2da0e9cd5/41392_2020_257_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/aa188c043fbe/41392_2020_257_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/7951a3b702f3/41392_2020_257_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/dd9db7f9b07a/41392_2020_257_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/594921198d59/41392_2020_257_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/feeb1c3e2973/41392_2020_257_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/13c2da0e9cd5/41392_2020_257_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/aa188c043fbe/41392_2020_257_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/7951a3b702f3/41392_2020_257_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/dd9db7f9b07a/41392_2020_257_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/594921198d59/41392_2020_257_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01fe/7644758/feeb1c3e2973/41392_2020_257_Fig6_HTML.jpg

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