title: Transactivated EGFR mediates α₁-AR-induced STAT3 activation and cardiac hypertrophy.
abstract: α(1)-Adrenergic receptor (α(1)-AR) is a crucial mediator of cardiac hypertrophy. Although numerous intracellular pathways have been implicated in α(1)-AR-induced hypertrophy, its precise mechanism remains elusive. We aimed to determine whether α(1)-AR induces cardiac hypertrophy through a novel signaling pathway-α(1)-AR/epidermal growth factor receptor (EGFR)/signal transducer and activator of transcription 3 (STAT3). The activation of STAT3 by α(1)-AR was first demonstrated by tyrosine phosphorylation, nuclear translocation, DNA binding, and transcriptional activity in neonatal Sprague-Dawley rat cardiomyocytes. Activated STAT3 showed an essential role in α(1)-AR-induced cardiomyocyte hypertrophic growth, as assessed by treatment with STAT3 inhibitory peptide and lentivirus-STAT3 small interfering RNA. The results were further confirmed by in vivo experiments involving intraperitoneal injection of the STAT3 inhibitor WP1066 significantly inhibiting phenylephrine-infusion-induced heart hypertrophy in male C57BL/6 mice. Furthermore, the α(1)-AR-activated STAT3 was associated with transactivation of EGFR because inhibition of EGFR with the selective inhibitor AG1478 prevented α(1)-AR-induced STAT3 tyrosine phosphorylation and its transcriptional activity, as well as cardiac hypertrophy. In summary, these results suggest that α(1)-AR induces the activation of STAT3, mainly through transactivation of EGFR, which plays an important role in α(1)-AR-induced cardiac hypertrophy.
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptide, Ministry of Health, Beijing, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Liao
authors.forename: Yao
authors.initials: Y
authors.lastname: Song
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Ma
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Lu
authors.forename: Zijian
authors.initials: Z
authors.lastname: Li
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010656:Phenylephrine; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014443:Tyrosine
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D047428:Protein Kinase Inhibitors; D018340:Receptors, Adrenergic, alpha-1; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D010656:Phenylephrine; D014443:Tyrosine; C541485:EGFR protein, mouse; C483803:Egfr protein, rat; D066246:ErbB Receptors; D051722:ADAM Proteins