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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  

Heo, Kyung-Sun (Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Ryoo, Sung-Woo (Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Kim, Lila (Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Nam, Miyoung (Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Baek, Seung-Tae (Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Lee, Hyemi (Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Lee, Ah-Reum (Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Park, Song-Kyu (Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology)
Park, Youngwoo (Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology)
Myung, Chang-Seon (Department of Pharmacy, Chungnam National University)
Kim, Dong-Uk (Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Hoe, Kwang-Lae (Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Publication Information
Molecules and Cells / v.26, no.5, 2008 , pp. 468-473 More about this Journal
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.
Keywords
$Cl^-$ channel; DIDS; Egr-1; low-density lipoprotein; PI3K;
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