title: HMG-CoA reductase inhibitors suppress intracellular calcium mobilization and membrane current induced by lysophosphatidylcholine in endothelial cells.
abstract: BACKGROUND
  Lysophosphatidylcholine (LPC) is known to increase intracellular Ca2+ concentration ([Ca2+]i) in endothelial cells. This study was conducted to investigate the effects of HMG-CoA reductase inhibitors (statins) on the increase in [Ca2+]i and membrane current induced by LPC.
  
  
  RESULTS
  [Ca2+]i was determined in cultured human aortic endothelial cells by fura-2 assay, and membrane current was measured by whole-cell patch clamp. The [Ca2+]i increase induced by LPC was abolished by inhibitors of phospholipase C (PLC). Statins markedly decreased the [Ca2+]i increase caused by LPC. This suppressive effect was quickly reversed by geranylgeranylpyrophosphate (GGPP) and was mimicked by inhibitors of Rho and Rho kinase. LPC induced the translocation of the GTP-bound active form of RhoA into membranes within 1 minute as determined by a pull-down assay and reduced the levels of RhoA in the cytoplasm, indicating that LPC quickly increases the GTP/GDP ratio of RhoA and induces membrane translocation. Statins prevented the GTP/GDP exchange of RhoA and its membrane translocation from the cytoplasm caused by LPC, and these effects of statins were reversed by GGPP. The responses of RhoA activation to statins and GGPP concurred with their effects on Ca2+ mobilization. LPC also induced a nonselective cation current after a lag. Statins prolonged the lag and decreased the current amplitude, and GGPP abolished the inhibitory effect on the current.
  
  
  CONCLUSIONS
  LPC induced Ca2+ mobilization and membrane current via a Rho activation-dependent PLC pathway in endothelial cells, and statins blocked these effects by preventing the GGPP-dependent lipid modification of Rho. The present study implicates Rho in LPC stimulation of Ca2+ movement.
authors.affiliation: First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ishibashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohkawara
authors.forename: Junko
authors.initials: J
authors.lastname: Kimura
authors.forename: Isao
authors.initials: I
authors.lastname: Matsuoka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Nagata
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Sotaro
authors.initials: S
authors.lastname: Sakurada
authors.forename: Yukio
authors.initials: Y
authors.lastname: Maruyama
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D001011:Aorta; D001905:Botulinum Toxins; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008244:Lysophosphatidylcholines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008798:Mevalonic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008244:Lysophosphatidylcholines; D011106:Polyisoprenyl Phosphates; D011725:Pyridines; C108830:Y 27632; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D010738:Type C Phospholipases; D001905:Botulinum Toxins; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid; D002118:Calcium