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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >EPAC activation inhibits acetaldehyde-induced activation and proliferation of hepatic stellate cell via Rap1
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EPAC activation inhibits acetaldehyde-induced activation and proliferation of hepatic stellate cell via Rap1

机译：EPAC激活通过Rap1抑制乙醛诱导的肝星状细胞的激活和增殖

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Hepatic stellate cells (HSCs) activation represents an essential event during alcoholic liver fibrosis (ALF). Previous studies have demonstrated that the rat HSCs could be significantly activated after exposure to 200 mu mol/L acetaldehyde for 48 h, and the cAMP/PKA signaling pathways were also dramatically upregulated in activated HSCs isolated from alcoholic fibrotic rat liver. Exchange protein activated by cAMP (EPAC) is a family of guanine nucleotide exchange factors (GEFs) for the small Ras-like GTPases Rap, and is being considered as a vital mediator of cAMP signaling in parallel with the principal cAMP target protein kinase A (PKA). Our data showed that both cAMP/PKA and cAMP/EPAC signaling pathways were involved in acetaldehyde-induced HSCs. Acetaldehyde could reduce the expression of EPAC1 while enhancing the expression of EPAC2. The cAMP analog Me-cAMP, which stimulates the EPAC/Rap1 pathway, could significantly decrease the proliferation and collagen synthesis of acetaldehyde-induced HSCs. Furthermore, depletion of EPAC2, but not EPAC1, prevented the activation of HSC measured as the production of alpha-SMA and collagen type I and III, indicating that EPAC1 appears to have protective effects on acetaldehyde-induced HSCs. Curiously, activation of PKA or EPAC perhaps has opposite effects on the synthesis of collagen and alpha-SMA: EPAC activation by Me-cAMP increased the levels of GTP-bound (activated) Rap1 while PKA activation by Phe-cAMP had no significant effects on such binding. These results suggested that EPAC activation could inhibit the activation and proliferation of acetaldehyde-induced HSCs via Rap1.
机译：肝星状细胞（HSC）激活代表酒精性肝纤维化（ALF）期间的重要事件。先前的研究表明，大鼠HSCs在暴露于200μmol / L乙醛中48 h后可以被显着激活，并且从酒精性纤维化大鼠肝中分离出的活化HSCs中cAMP / PKA信号通路也被显着上调。 cAMP（EPAC）激活的交换蛋白是小型Ras样GTPases Rap的鸟嘌呤核苷酸交换因子（GEF）家族，与主要cAMP目标蛋白激酶A（）并行，被认为是cAMP信号的重要介体。 PKA）。我们的数据表明，cAMP / PKA和cAMP / EPAC信号通路均参与乙醛诱导的HSC。乙醛可以降低EPAC1的表达，同时增强EPAC2的表达。 cAMP类似物Me-cAMP刺激EPAC / Rap1通路，可显着降低乙醛诱导的HSC的增殖和胶原合成。此外，耗尽EPAC2而不是EPAC1阻止了HSC的活化，该活化被测量为产生α-SMA和I型和III型胶原，表明EPAC1似乎对乙醛诱导的HSC具有保护作用。奇怪的是，PKA或EPAC的激活可能对胶原蛋白和α-SMA的合成有相反的影响：Me-cAMP的EPAC激活增加了GTP结合（激活）的Rap1的水平，而Phe-cAMP的PKA激活对GTP结合的激活没有明显影响这样的约束力。这些结果表明，EPAC激活可通过Rap1抑制乙醛诱导的HSC的激活和增殖。

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