Fan Chunyuan, Katsuyama Masato, Nishinaka Toru, Yabe-Nishimura Chihiro
Department of Pharmacology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto 602-8566, Japan.
FEBS Lett. 2005 Feb 14;579(5):1301-5. doi: 10.1016/j.febslet.2005.01.021. Epub 2005 Jan 26.
We previously reported that hypertrophy of vascular smooth muscle cells caused by prostaglandin (PG) F2alpha is mediated by the induction of NOX1, a catalytic subunit of NADPH oxidase that generates superoxide. The signal transduction pathway(s) involved in this process, however, remained unresolved. PGF2alpha enhanced the phosphorylation of the epidermal growth factor (EGF) receptor, and a selective inhibitor of EGF receptor kinase, tyrphostin AG1478, significantly suppressed PGF2alpha-induced NOX1 expression. AG1478 also blunted the PGF2alpha-induced phosphorylation of extracellular signal-regulated protein kinase (ERK)1/2 and Akt. Phosphoinositide 3 (PI3) kinase inhibitors not only reduced PGF2alpha-induced NOX1 expression, but also suppressed the phosphorylation of ATF-1, a transcription factor previously shown to play a key role in the induction of NOX1. Accordingly, the transactivation of the EGF receptor and the activation of ERK1/2, PI3 kinase, and ATF-1 constitute the signaling pathways involved in the upregulation of NOX1.
我们之前报道过，前列腺素（PG）F2α 引起的血管平滑肌细胞肥大是由NADPH氧化酶的催化亚基NOX1的诱导介导的，该酶可产生超氧化物。然而，参与这一过程的信号转导途径仍未明确。PGF2α 增强了表皮生长因子（EGF）受体的磷酸化，而EGF受体激酶的选择性抑制剂 tyrphostin AG1478显著抑制了PGF2α 诱导的NOX1表达。AG1478还减弱了PGF2α 诱导的细胞外信号调节蛋白激酶（ERK）1/2和Akt的磷酸化。磷脂酰肌醇3（PI3）激酶抑制剂不仅降低了PGF2α 诱导的NOX1表达，还抑制了ATF-1的磷酸化，ATF-1是一种转录因子，之前已证明在NOX1的诱导中起关键作用。因此，EGF受体的反式激活以及ERK1/2、PI3激酶和ATF-1的激活构成了参与NOX1上调的信号通路。
