title: EPAC activation inhibits acetaldehyde-induced activation and proliferation of hepatic stellate cell via Rap1.
abstract: 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.
authors: a School of Pharmacy, Anhui Medical University, Meishan Road, Hefei, Anhui Province 230032, China.|b Institute for Liver Disease of Anhui Medical University, Meishan Road, Hefei, Anhui Province 230032, China.
authors: Yan
authors: Y
authors: Yang
authors: a School of Pharmacy, Anhui Medical University, Meishan Road, Hefei, Anhui Province 230032, China.|b Institute for Liver Disease of Anhui Medical University, Meishan Road, Hefei, Anhui Province 230032, China.
authors: Feng
authors: F
authors: Yang
authors: a School of Pharmacy, Anhui Medical University, Meishan Road, Hefei, Anhui Province 230032, China.|b Institute for Liver Disease of Anhui Medical University, Meishan Road, Hefei, Anhui Province 230032, China.
authors: Xiaojuan
authors: X
authors: Wu
authors: a School of Pharmacy, Anhui Medical University, Meishan Road, Hefei, Anhui Province 230032, China.|b Institute for Liver Disease of Anhui Medical University, Meishan Road, Hefei, Anhui Province 230032, China.
authors: Xiongwen
authors: X
authors: Lv
authors: a School of Pharmacy, Anhui Medical University, Meishan Road, Hefei, Anhui Province 230032, China.|b Institute for Liver Disease of Anhui Medical University, Meishan Road, Hefei, Anhui Province 230032, China.
authors: Jun
authors: J
authors: Li
mesh_terms: D000079:Acetaldehyde / Q000037:antagonists & inhibitors / Q000633:toxicity; D000199:Actins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D024043:Collagen Type II / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000819:agonists / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D034622:RNA Interference; D051381:Rats; D015290:Second Messenger Systems / Q000187:drug effects; D020827:rap1 GTP-Binding Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000079:Acetaldehyde; D000199:Actins; D024042:Collagen Type I; D024043:Collagen Type II; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020662:Guanine Nucleotide Exchange Factors; D020827:rap1 GTP-Binding Proteins; C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; C483758:N(6)-phenyl-cAMP; C526973:Rapgef3 protein, rat; C531571:Rapgef4 protein, rat; C498862:Acta2 protein, rat
keywords: EPAC1; EPAC2; Rap1; acetaldehyde; acétaldéhyde; cellules de Kupffer; hepatic stellate cells