title: Inhibition of infarction-induced sympathetic innervation with endothelin receptor antagonism via a PI3K/GSK-3β-dependent pathway.
abstract: 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 ETAreceptor antagonist) or A-192621 (an ETBreceptor 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. ETAreceptor 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.
authors.affiliation: Department of Medicine, Cardiology Section, China Medical University-An Nan Hospital, Tainan, Taiwan.|Department of Medicine, China Medical University, Taichung, Taiwan.|Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: T-M
authors.initials: TM
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Nen-Chung
authors.initials: NC
authors.lastname: Chang
authors.affiliation: Department of Neurosurgery, Bioinnovation Center, Tzu Chi foundation, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan.
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D000077868:Atrasentan; D015153:Blotting, Western; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006321:Heart / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D011897:Random Allocation; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
chemical_list: C120508:A 192621; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D017466:Receptors, Endothelin; D020932:Nerve Growth Factor; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D000077868:Atrasentan; D009638:Norepinephrine