Transactivated EGFR mediates α 1 -AR-induced STAT3 activation and cardiac hypertrophy

• Published in: American journal of physiology. Heart and circulatory physiology 2011-11, Vol.301 (5), p.H1941-H1951
• Main Authors: Li, Yan, Zhang, Hui, Liao, Wenqiang, Song, Yao, Ma, Xiaowei, Chen, Chao, Lu, Zhizhen, Li, Zijian, Zhang, Youyi
• Format: Article
• Language: English
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00338.2011

Li Y, Zhang H, Liao W, Song Y, Ma X, Chen C, Lu Z, Li Z, Zhang Y. 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.