Inhibition of infarction-induced sympathetic innervation with endothelin receptor antagonism via a PI3K/GSK-3β-dependent pathway

T. M. Lee, Nen Chung Chang, Shinn Zong Lin

研究成果: 雜誌貢獻文章同行評審

9 引文 斯高帕斯(Scopus)

摘要

Although endothelin (ET)-1 has been shown to upregulate nerve growth factor (NGF) expression, the molecular mechanisms are largely unknown. Phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase (GSK)-3β signal has been implicated in the regulation of NGF. We investigated whether selective ET receptor blockers attenuated cardiac sympathetic reinnervation through restoring PI3K/Akt/GSK-3β activity. After ligation of the left anterior descending artery, male Wistar rats were randomized to either vehicle, atrasentan (an ETA receptor antagonist) or A-192621 (an ETB receptor antagonist) for 4 weeks. Sympathetic hyperinnervation after infarction was confirmed by myocardial norepinephrine measurement and immunofluorescent analysis. Post infarction was associated with increased reactive oxygen species (ROS), as measured by myocardial superoxide levels and dihydroethidine fluorescence staining. This was paralleled by a significant upregulation of NGF expression on mRNA and protein levels in the vehicle-treated rats, which reduced after administering atrasentan, not A-192621. Arrhythmic scores in the vehicle-treated rats were significantly higher than those treated with atrasentan. In an in vivo study atrasentan-induced decreased NGF was associated with activation of PI3K/Akt signaling pathway, which was further confirmed by the ex vivo study showing the restoration of NGF levels after coadministration of PI3K inhibitors (wortmannin and LY294002). Lithium chloride, an inhibitor of GSK-3β, did not provide additional attenuated NGF levels compared with atrasentan alone. Finally, atrasentan-attenuated NGF levels were reversed in the presence of peroxynitrite generator. ETA receptor antagonism is a mediator to attenuate sympathetic hyperinnervation probably through restoration of PI3K/Akt/GSK-3β/ROS signaling pathway, a potential pharmacological target for arrhythmias after infarction.

原文英語
頁(從 - 到)243-255
頁數13
期刊Laboratory Investigation
97
發行號3
DOIs
出版狀態已發佈 - 三月 1 2017

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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