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

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.

SUBMITTER: Chen E

PROVIDER: S-EPMC7644758 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Chen Erya E Chen Chan C Niu Zhendong Z Gan Lu L Wang Qiao Q Li Ming M Cai XingWei X Gao Rui R Katakam Sruthi S Chen Hai H Zhang Shu S Zhou Ronghua R Cheng Xu X Qiu Yanhua Y Yu Hai H Zhu Tao T Liu Jin J

Signal transduction and targeted therapy 20201106 1

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 ...[more]

PMID: 33154351

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Project description:BackgroundIschemia stroke is the leading cause of disability, which is a consequence of vascular occlusion. The purpose of this study is to investigate the effect of cornin which is isolated from the fruit of Verbena officinalis L, against astrocytes autophagy induced by cerebral ischemia/reperfusion (CI/R) injury in vitro and in vivo and its potential mechanism.MethodsCornin at dose of 2.5, 5 and 10 mg/kg were intravenously injected to MCAO rats at 15 min after reperfusion. The infarction volume, blood-brain barrier (BBB), neurological severity score (mNSS), and autophagy related protein were used to evaluated the protective effects and potential mechanism of cornin in autophagy with or without phosphoinositide-3 kinase (PI3K)inhibitor LY294002 and mammalian target of rapamycin (mTOR) small interfering RNA (siRNA) at 24 h after CI/R injury. The potential protective effects and mechanism of cornin at concention of 10 ~ 1000 nM were also evaluated in oxygen glucose deprivation/reperfusion (OGD/R) in U87 cells.ResultsThe results suggest that cornin at dose of 5 or 10 mg/kg significantly reduce the cerebral infarction volume and blood-brain barrier (BBB) leakage, and improve neurological recovery in MCAO rats. Cleaved caspase-3 and Bax levels were significantly decreased, while B-cell lymphoma-2 (Bcl-2) and the apoptosis regulator ratio (Bcl-2/Bax) were markedly increased when treated with 2.5-10 mg/kg cornin. The obvious decreased expressions of glial fibrillary acidic protein (GFAP), myosin-like BCL2 interacting protein (Beclin-1) and microtubule-associated protein light chain 3 II (LC3-II) and increased of neuronal nuclei (NeuN), sequestosome-1 (p62), phosphorylated mTOR (p-mTOR), and phosphorylated Akt (p-Akt) were observed in MCAO rats treated with 10 mg/kg cornin, which was counteracted by LY294002. The expression of autophagy-related proteins with or without LY294002 and mTOR siRNA presented the similar results as in vitro in OGD/R in U87 cells.ConclusionsThese results indicate that cornin improved neurological recovery after cerebral ischemia injury by preventing astrocytes autophagy induced by CI/R via the PI3K/Akt/mTOR signaling pathway.

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Dataset Information

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

Publications

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

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