title: Cl- -channel is essential for LDL-induced cell proliferation via the activation of Erk1/2 and PI3k/Akt and the upregulation of Egr-1 in human aortic smooth muscle cells.
abstract: Low-density lipoprotein (LDL) induces cell proliferation in human aortic smooth muscle cells (hAoSMCs), which may be involved in atherogenesis and intimal hyperplasia. Recent studies have demonstrated that Cl- channels are related to vessel cell proliferation induced by a variety of stimuli. In this study, we investigated a potential role of Cl-channels in the signaling pathway of LDL effects on hAoSMC proliferation with a focus on the activation of Erk1/2-PI3K/Akt and the subsequent upregulation of Egr-1. Cl- channel blockers, DIDS, but neither NPPB nor Furosemide, completely abolished the LDL-induced DNA synthesis and cell proliferation. Moreover, DIDS, but not NPPB, significantly decreased LDL-stimulated Cl- concentration, as judged by flow cytometry analysis using MQAE as a Cl- -detection dye. DIDS pretreatment completely abolished the activation of Erk1/2 and PI3K/Akt in a dose-dependent manner that is the hallmark of LDL activation, as judged by Western blot and proliferation assays. Moreover, pretreatment with DIDS (Cl- channel blockers) but not LY294002 (PI3K inhibitors) completely abolished the LDL-induced upregulation of Egr-1 to the same extent as PD98059 (MEK inhibitors to inhibit Erk), as judged by Western blot and luciferase reporter assays. This is the first report, to our knowledge, that DIDS-sensitive Cl- channels play a key role in the LDL-induced cell proliferation of hAoSMCs via the activation of Erk1/2 and PI3K/Akt and the upregulation of Egr-1.
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
authors: Kyung-Sun
authors: KS
authors: Heo
authors: Sung-Woo
authors: SW
authors: Ryoo
authors: Lila
authors: L
authors: Kim
authors: Miyoung
authors: M
authors: Nam
authors: Seung-Tae
authors: ST
authors: Baek
authors: Hyemi
authors: H
authors: Lee
authors: Ah-Reum
authors: AR
authors: Lee
authors: Song-Kyu
authors: SK
authors: Park
authors: Youngwoo
authors: Y
authors: Park
authors: Chang-Seon
authors: CS
authors: Myung
authors: Dong-Uk
authors: DU
authors: Kim
authors: Kwang-Lae
authors: KL
authors: Hoe
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018118:Chloride Channels; D008078:Cholesterol, LDL; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid