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.
Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H1941-51. doi: 10.1152/ajpheart.00338.2011. Epub 2011 Aug 19.
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.
α(1)-肾上腺素能受体 (α(1)-AR) 是心脏肥大的关键介质。虽然许多细胞内途径都与 α(1)-AR 诱导的肥大有关,但确切的机制仍不清楚。我们旨在确定 α(1)-AR 是否通过一种新的信号通路-α(1)-AR/表皮生长因子受体 (EGFR)/信号转导和转录激活因子 3 (STAT3) 诱导心脏肥大。首先通过酪氨酸磷酸化、核易位、DNA 结合和转录活性证明了 α(1)-AR 对 STAT3 的激活作用在新生 Sprague-Dawley 大鼠心肌细胞中。STAT3 抑制剂肽和慢病毒-STAT3 小干扰 RNA 的处理表明,激活的 STAT3 在 α(1)-AR 诱导的心肌细胞肥大生长中起着重要作用。体内实验进一步证实了这一结果,其中腹腔注射 STAT3 抑制剂 WP1066 显著抑制了雄性 C57BL/6 小鼠中苯肾上腺素输注诱导的心脏肥大。此外,α(1)-AR 激活的 STAT3 与 EGFR 的跨激活有关,因为用选择性抑制剂 AG1478 抑制 EGFR 可防止 α(1)-AR 诱导的 STAT3 酪氨酸磷酸化及其转录活性以及心脏肥大。总之,这些结果表明,α(1)-AR 诱导 STAT3 的激活,主要通过 EGFR 的跨激活,在 α(1)-AR 诱导的心脏肥大中起重要作用。