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Inhibition of Endothelin Receptors on Sympathetic Innervation via a PI3K/Akt‐dependent Pathway in Post‐infarcted Rats
Author(s) -
Lee TsungMing,
Chen WeiTing
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.831.1
Subject(s) - endothelin receptor , receptor , pi3k/akt/mtor pathway , protein kinase b , medicine , endothelin 1 , sympathetic innervation , endocrinology , chemistry , microbiology and biotechnology , signal transduction , biology
Although endothelin (ET)‐1 has been shown to upregulate nerve growth factor (NGF) expression after myocardial infarction, the molecular mechanisms are largely unknown. We investigated whether selective ET receptor blockers attenuate cardiac sympathetic reinnervation through restoring phosphatidylinositol 3‐kinase (PI3K)/Akt/glycogen synthase kinase (GSK)‐3β activity. Twenty‐four hours after coronary ligation, male Wistar rats were randomized to either vehicle, ABT‐627 (an ET A receptorantagonist), or A‐192621 (an ET B receptorantagonist) for 4 weeks. Sympathetic hyperinnervation after infarction was confirmed by myocardial norepinephrine measurement and immunofluorescent analysis. This was paralleled by a significant upregulation of NGF protein and mRNA in the vehicle‐treated rats, which reduced after administering ABT‐627, not A‐192621. Arrhythmic scores during programmed stimulation in the vehicle‐treated rats were significantly higher than those treated with ABT‐627. In an in vivo study NGF was significantly decreased through activation of PI3K/Akt signaling pathway in the presence of ABT‐627, which was also confirmed by the ex vivo study showing the increased NGF levels by the use of PI3K inhibitors (wortmannin and LY294002). Furthermore, lithium chloride, an inhibitor of GSK‐3β, decreased NGF levels, suggesting the involvement of GSK‐3β as a downstream molecule of PI3K/Akt pathways. These data demonstrate that the ET A receptor antagonism is a critical mediator to attenuate sympathetic hyperinnervation probably through the restoration of PI3K/Akt/GSK‐3β signaling. Inhibition of GSK‐3β‐mediated pathways is novel regulators of sympathetic innervation and potential pharmacological targets for arrhythmias.