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α₁-AR 诱导的 STAT3 激活和心脏肥大由 EGFR 转导介导。

Transactivated EGFR mediates α₁-AR-induced STAT3 activation and cardiac hypertrophy.

机构信息

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.

出版信息

Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H1941-51. doi: 10.1152/ajpheart.00338.2011. Epub 2011 Aug 19.

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.

摘要

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。

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