EPAC activation inhibits acetaldehyde-induced activation and proliferation of hepatic stellate cell via Rap1.
EPAC activation inhibits acetaldehyde-induced activation and proliferation of hepatic stellate cell via Rap1.
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DOI：
10.1139/cjpp-2015-0437
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发表时间：
2016-05
影响因子：
2.1
通讯作者：
Yan Yang;Feng Yang;Xiaojuan Wu;Xiongwen Lv;Jun Li
中科院分区：
文献类型：
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作者：
Yan Yang;Feng Yang;Xiaojuan Wu;Xiongwen Lv;Jun Li
肝星状细胞（HSC）激活是酒精性肝纤维化（ALF）过程中的一个重要事件。前期研究表明，200 μmol/L乙醛暴露48 h后，大鼠HSCs可显着激活，且酒精性纤维化大鼠肝脏中分离的活化HSCs中cAMP/PKA信号通路也显着上调。 cAMP 激活的交换蛋白 (EPAC) 是小 Ras 样 GTPases Rap 的鸟嘌呤核苷酸交换因子 (GEF) 家族，被认为是与主要 cAMP 靶蛋白激酶 A (PKA) 并行的 cAMP 信号转导的重要介质。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 的增殖和胶原蛋白合成。此外，EPAC2（而非EPAC1）的消耗阻止了HSC的激活（测量为α-SMA以及I型和III型胶原蛋白的产生），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 的合成产生相反的影响：Me-cAMP 激活 EPAC 增加了 GTP 结合（激活）Rap1 的水平，而 Phe-cAMP 激活 PKA 对这种结合没有显着影响。这些结果表明EPAC激活可以通过Rap1抑制乙醛诱导的HSC的激活和增殖。
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 μmol/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 α-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 α-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.