Myocardial infarction induces sympathetic hyperinnervation via a nuclear factor-κB-dependent pathway in rabbit hearts

Wang, Ye; Suo, Fei; Liu, Ju; Hu, Hesheng; Xue, Mei; Cheng, Wen-Chieh; Xuan, Yongli; Yan, Shi Fang

doi:10.1016/j.neulet.2012.12.059

Cited by 25 publications

(27 citation statements)

References 34 publications

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“…The nuclear protein levels of NF‐κB p65 at the infarcted border were higher after MI compared to sham‐operated hearts ( P <.01 for both, Figure A). Moreover, consistent with previous studies, the IκBα levels were downregulated (Figure B), which indicated that MI‐induced NF‐κB nuclear translocation in an IκBα‐dependent manner . P2X7R RNAi inhibited the degradation of IκBα and prevented the translocation of NF‐κB into the nucleus (Figure A‐D).…”

Section: Resultssupporting

confidence: 90%

“…Activated NF‐κB has been detected in post‐MI remodeling . Our previous work showed that MI activated NF‐κB, represented by an increase in NF‐κB p65 protein levels, while inhibiting NF‐κB activation ameliorated sympathetic regeneration by downregulating NGF levels . A previous study reported that purinergic signals could activate NF‐κB through the P2X 7 receptor by selectively targeting NF‐κB p65.…”

Section: Introductionmentioning

confidence: 97%

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Targeted P2X₇R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction

Gao

Yin

Shi

et al. 2017

Cardiovascular Therapeutics

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 97%

Targeted P2X₇R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction

Gao

Yin

Shi

et al. 2017

Cardiovascular Therapeutics

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“…In the present study, we aimed to determine the mechanisms by Several studies have provided evidence that an inflammatory reaction following MI is a prerequisite for healing and scar formation. In addition, sympathetic nerve sprouting following MI has been shown to be closely associated with inflammatory processes, 4,5,32,33 which result in the local synthesis of NGF synthesis by inflammatory cells, including macrophages and myofibroblasts. NGF, a potent neural chemoattractant, has been recognized as an important factor in nerve sprouting and differentiation, survival, and synaptic activity of sympathetic nerves during the process of cardiac injury.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence indicates that sympathetic nerve sprouting is closely related to the inflammatory response and is primarily observed at infarct borders, where numerous macrophages and inflammatory factors are present. 4,5 Nerve growth factor (NGF) upregulated by MI-induced inflammation is the principal factor inducing sympathetic nerve sprouting and remodeling after MI. 6 Macrophages, as important immune cells, are involved throughout the entire process of inflammation.…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin attenuates sympathetic hyperinnervation together with the augmentation of M2 macrophages in rats postmyocardial infarction

Yang

Cheng

et al. 2016

Cardiovascular Therapeutics

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SummaryObjectives: Inflammation after myocardial infarction (MI) causes cardiac nerve sprouting and consequent ventricular arrhythmias (VAs). Macrophages, as major immune cells, are involved in the entire inflammation response process and serve as a link between inflammation and sympathetic hyperinnervation by regulating nerve growth factor (NGF) expression. Accumulating evidence shows that statins possess antiarrhythmogenic properties, and the aim of this study was to explore the mechanism by which atorvastatin ameliorates cardiac sympathetic nerve sprouting via regulating macrophage polarization.Methods: Rat models of MI were created by ligating the left coronary artery.MI-operated rats received either atorvastatin or phosphate-buffered saline for 7 days. Immunohistochemical analyses and immunofluorescence staining were used to analyze macrophage infiltration after MI and to detect the distribution and density of growth-associated protein-43 (GAP-43) and tyrosine hydroxylase (TH) in nerve fibers in peri-infarct zones after MI. The polarity of the macrophages that were obtained from the rat peritoneal cavity was examined via flow cytometry. The protein levels of NGF were detected via Western blot analysis, and the concentrations of NGF in the supernatants were determined via enzyme-linked immunosorbent assay. The mRNA levels of NGF, inducible nitric oxide synthase (iNOS), Arginase-1 (Arg1), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) were examined by quantitative real-time polymerase chain reaction. The association between VAs and MI was evaluated using programmed electrophysiological stimulation.Results: Macrophages were successfully induced to the M1 (classically activated) and M2 (alternatively activated) phenotypes by stimulation with lipopolysaccharide and interferon-γ (LPS + IFN-γ) and interleukin-4 (IL-4), respectively. Atorvastatin markedly downregulated IL-1β, TNF-α, iNOS, and NGF and upregulated Arg1, shifting the macrophage phenotype from M1 to M2. Moreover, atorvastatin significantly reduced TH levels and the density of GAP-43-positive nerve fibers and decreased inducible VAs.

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“…and Alexa 545‐conjugated goat anti‐rabbit (1:100; Pepro Rocky Hill, NJ, USA) secondary antibodies. We analysed four sections adjacent to the Masson's trichrome‐strained set to evaluate sympathetic innervation density; the first section taken for the analysis was 1.5–2 mm apical to the ligation . The density of nerve is expressed as the ratio of labelled nerve fibre area to total area (m 2 /mm 2 ), while papillary muscles were excluded from the study because a variable sympathetic innervation has been reported.…”

Section: Methodsmentioning

confidence: 99%

P2X₇ receptor inhibition attenuated sympathetic nerve sprouting after myocardial infarction via the NLRP3/IL‐1β pathway

Yin

Wang

et al. 2017

J Cellular Molecular Medi

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Mounting evidence supports the hypothesis that inflammation modulates sympathetic sprouting after myocardial infarction (MI). The myeloid P2X7 signal has been shown to activate the nucleotide‐binding and oligomerization domain‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome, a master regulator of inflammation. We investigated whether P2X7 signal participated in the pathogenesis of sympathetic reinnervation after MI, and whether NLRP3/interleukin‐1β (IL‐1β) axis is involved in the process. We explored the relationship between P2X7 receptor (P2X7R) and IL‐1β in the heart tissue of lipopolysaccharide (LPS)‐primed naive rats. 3′‐O‐(4‐benzoyl) benzoyl adenosine 5′‐triphosphate (BzATP), a P2X7R agonist, induced caspase‐1 activation and mature IL‐1β release, which was further neutralized by a NLRP3 inhibitor (16673‐34‐0). MI was induced by coronary artery ligation. Following infarction, a marked increase in P2X7R was localized within infiltrated macrophages and observed in parallel with an up‐regulation of NLRP3 inflammasome levels and the release of IL‐1β in the left ventricle. The administration of A‐740003 (a P2X7R antagonist) significantly prevented the NLRP3/IL‐1β increase. A‐740003 and/or Anakinra (an IL‐1 receptor antagonist) significantly reduced macrophage infiltration as well as macrophage‐based IL‐1β and NGF (nerve growth factor) production and eventually blunted sympathetic hyperinnervation, as assessed by the immunofluorescence of tyrosine hydroxylase (TH) and growth‐associated protein 43 (GAP 43). Moreover, the use of Anakinra partly attenuated sympathetic sprouting. This indicated that the effect of P2X7 on neural remodelling was mediated at least partially by IL‐1β. The arrhythmia score of programmed electric stimulation was in accordance with the degree of sympathetic hyperinnervation. In vitro studies showed that BzATP up‐regulated secretion of nerve growth factor (NGF) in M1 macrophages via IL‐1β. Together, these data indicate that P2X7R contributes to neural and cardiac remodelling, at least partly mediated by NLRP3/IL‐1β axis. Therapeutic interventions targeting P2X7 signal may be a novel approach to ameliorate arrhythmia following MI.

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Myocardial infarction induces sympathetic hyperinnervation via a nuclear factor-κB-dependent pathway in rabbit hearts

Cited by 25 publications

References 34 publications

Targeted P2X₇R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction

Targeted P2X₇R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction

Atorvastatin attenuates sympathetic hyperinnervation together with the augmentation of M2 macrophages in rats postmyocardial infarction

P2X₇ receptor inhibition attenuated sympathetic nerve sprouting after myocardial infarction via the NLRP3/IL‐1β pathway

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Myocardial infarction induces sympathetic hyperinnervation via a nuclear factor-κB-dependent pathway in rabbit hearts

Cited by 25 publications

References 34 publications

Targeted P2X7R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction

Targeted P2X7R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction

Atorvastatin attenuates sympathetic hyperinnervation together with the augmentation of M2 macrophages in rats postmyocardial infarction

P2X7 receptor inhibition attenuated sympathetic nerve sprouting after myocardial infarction via the NLRP3/IL‐1β pathway

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Targeted P2X₇R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction

Targeted P2X₇R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction

P2X₇ receptor inhibition attenuated sympathetic nerve sprouting after myocardial infarction via the NLRP3/IL‐1β pathway