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TLR4 participates in sympathetic hyperactivity Post-MI in the PVN by regulating NF-?B pathway and ROS production.

ABSTRACT: Sympathetic nerve hyperactivity is a primary reason for fatal ventricular arrhythmias (VAs) following myocardial infarction (MI). Pro-inflammatory cytokines produced in the paraventricular nucleus (PVN) post-MI are associated with sympathetic overexcitation; however, the precise mechanism needs further investigation. Our aim was to explore the mechanism of toll-like receptor 4 (TLR4) and its downstream molecular pathway in mediating sympathetic activity post-MI within the PVN. A rat MI model was developed via left anterior descending coronary artery ligation. TLR4 was primarily localized in microglia and increased markedly within the PVN at 3 days in MI rats. Sympathoexcitation also increased, as indicated by high levels of renal sympathetic nerve activity (RSNA) and norepinephrine (NE) concentration. TLR4 knockdown via shRNA microinjection to the PVN resulted in decreased activation of Fos protein (+) neurons in the PVN and peripheral sympathetic nerve activity. TLR4 knockdown also exhibited a lower arrhythmia score following programmed electrical stimulation than those treated with MI surgery only, indicating that the knockdown of TLR4 decreased the incidence of malignant ventricular arrhythmias following MI. LPS-induced inflammatory response was analyzed to explore the underlying mechanism of TLR4 in sympathetic hyperactivity. High levels of NF-?B protein, the pro-inflammatory cytokines IL-1? and TNF-?, and ROS production were observed in the LPS group. PVN-targeted injection of the NF-?B inhibitor PDTC attenuated NF-?B expression and sympathetic activity. Taken together, the results suggested that knockdown of microglial TLR4 within the PVN decreased sympathetic hyperactivity and subsequent VAs post-MI. The downstream NF-?B pathway and ROS production participated in the process. Interventions targeting TLR4 signaling in the PVN may be a novel approach to ameliorate the incidence of VAs post-MI.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6460304 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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TLR4 participates in sympathetic hyperactivity Post-MI in the PVN by regulating NF-κB pathway and ROS production.

Wang Yu Y Hu Hesheng H Yin Jie J Shi Yugen Y Tan Jiayu J Zheng Lu L Wang Cailing C Li Xiaolu X Xue Mei M Liu Ju J Wang Ye Y Li Yan Y Li Xinran X Liu Fuhong F Liu Qiang Q Yan Suhua S

Redox biology 20190402

Sympathetic nerve hyperactivity is a primary reason for fatal ventricular arrhythmias (VAs) following myocardial infarction (MI). Pro-inflammatory cytokines produced in the paraventricular nucleus (PVN) post-MI are associated with sympathetic overexcitation; however, the precise mechanism needs further investigation. Our aim was to explore the mechanism of toll-like receptor 4 (TLR4) and its downstream molecular pathway in mediating sympathetic activity post-MI within the PVN. A rat MI model was ...[more]

PMID: 30978539

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Project description:BackgroundAccelerated cellular senescence within the nucleus pulposus (NP) region is a common feature of disc degeneration. Our previous work indicated that TNF-α promoted NP cell senescence. Although the intervertebral disc has been reported to be an estrogen-sensitive tissue, it is unclear whether estrogen can inhibit premature senescence of NP cells.ObjectiveTo investigate whether 17beta-estradiol (E2) can attenuate TNF-α-induced premature senescence of NP cells and the potential mechanism behind this regulatory process.MethodsIsolated NP cells and intact intervertebral discs from healthy rats were cultured with or without TNF-α, E2 or their combination. The pan estrogen receptor (ER) antagonist ICI 182780 was used to investigate the role of ER. Direct and indirect indicators including cell proliferation, SA-β-Gal activity, telomerase activity, cell cycle, and the expression of matrix macromolecules (aggrecan and collagen II) and senescence markers (p16 and p53) were used to evaluate the premature senescence of NP cells. Additionally, intracellular reactive oxygen species (ROS) and NF-κB/p65 activity were also detected in the NP cell cultures.ResultsIn the NP cell cultures, E2 significantly increased cell proliferation potency, telomerase activity and the expression of matrix macromolecules but attenuated SA-β-Gal activity, senescence marker (p53 and p16) expression and G1 cycle arrest in TNF-α-treated NP cells. Furthermore, E2 inhibited ROS generation and phospho-NF-κB/p65 expression in the TNF-α-treated NP cells. However, the ER antagonist ICI 182780 abolished the effects of E2 on TNF-α-treated NP cells. In the disc organ cultures, E2 also significantly increased matrix synthesis, whereas it decreased senescence marker (p53 and p16) expression, which could be abolished by the ER antagonist ICI 182780.ConclusionThe interaction between E2 and ER can attenuate TNF-α-induced premature senescence of rat NP cells through interfering with the ROS/NF-κB pathway.

Dataset Information

TLR4 participates in sympathetic hyperactivity Post-MI in the PVN by regulating NF-?B pathway and ROS production.

Publications

TLR4 participates in sympathetic hyperactivity Post-MI in the PVN by regulating NF-κB pathway and ROS production.

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