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Deprecated: Implicit conversion from float 261.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Cell+Mol+Med 2017 ; 21 (11): 2695-710 Nephropedia Template TP
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P2X7 receptor inhibition attenuated sympathetic nerve sprouting after myocardial infarction via the NLRP3/IL?1? pathway #MMPMID28470940
Yin J; Wang Y; Hu H; Li X; Xue M; Cheng W; Wang Y; Li X; Yang N; Shi Y; Yan S
J Cell Mol Med 2017[Nov]; 21 (11): 2695-710 PMID28470940show ga
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?1? (IL?1?) axis is involved in the process. We explored the relationship between P2X7 receptor (P2X7R) and IL?1? 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?1? 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?1? in the left ventricle. The administration of A?740003 (a P2X7R antagonist) significantly prevented the NLRP3/IL?1? increase. A?740003 and/or Anakinra (an IL?1 receptor antagonist) significantly reduced macrophage infiltration as well as macrophage?based IL?1? 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?1?. 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?1?. Together, these data indicate that P2X7R contributes to neural and cardiac remodelling, at least partly mediated by NLRP3/IL?1? axis. Therapeutic interventions targeting P2X7 signal may be a novel approach to ameliorate arrhythmia following MI.
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J+Cell+Mol+Med 2017 ; 21 (11): 2695-710
