Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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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)
  • Received : 2008.04.30
  • Accepted : 2008.08.14
  • Published : 2008.11.30
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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

References

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