title: Eukaryotic elongation factor 2 kinase controls proliferation and migration of vascular smooth muscle cells.
abstract: OBJECTIVE
  Eukaryotic elongation factor 2 kinase (eEF2K), also known as calmodulin (CaM)-dependent protein kinase (CaMK) III, is a unique member of CaMK family protein. We have recently found that expression of eEF2K protein increased in mesenteric artery from spontaneously hypertensive rats. As pathogenesis of hypertension is in part regulated by vascular structural remodelling via proliferation and migration of vascular smooth muscle cells (SMCs), we tested the hypothesis that eEF2K controls SMCs proliferation and migration.
  In rat mesenteric arterial SMCs, an eEF2K inhibitor, A-484954 (10 μm), significantly inhibited platelet-derived growth factor (PDGF)-BB (10 ng mL(-1) )-induced SMCs proliferation as determined by a cell counting and bromodeoxyuridine incorporation assay. PDGF-BB (10 ng mL(-1) )-induced SMCs migration was significantly inhibited by A-484954 (10 μm) as determined by a Boyden chamber assay. A-484954 (10 μm) significantly inhibited PDGF-BB (10 ng mL(-1) )-induced phosphorylation of eEF2K, extracellular signal-regulated kinase (ERK), Akt, p38 and heat-shock protein (HSP) 27 as determined by Western blotting. It was confirmed that a CaM inhibitor, W-7 (50 μm), inhibited PDGF-BB (10 ng mL(-1) )-induced phosphorylation of eEF2K. In an ex vivo mesenteric arterial ring assay, 10% foetal bovine serum-induced SMCs outgrowth was significantly inhibited by A-484954 (10 μm).
  
  
  CONCLUSIONS
  We for the first time revealed that eEF2K mediates PDGF-BB-induced SMCs proliferation and migration through activating ERK, Akt, p38 and HSP27 signals in a CaM-dependent manner. Our results suggest eEF2K as a novel pharmaceutical target for the prevention of hypertensive cardiovascular diseases.
authors: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan.
authors: T
authors: T
authors: Usui
authors: R
authors: R
authors: Nijima
authors: T
authors: T
authors: Sakatsume
authors: K
authors: K
authors: Otani
authors: S
authors: S
authors: Kameshima
authors: M
authors: M
authors: Okada
authors: H
authors: H
authors: Yamawaki
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D018832:Molecular Chaperones; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010982:Platelet-Derived Growth Factor; C517690:Eef2k protein, mouse; D054736:Elongation Factor 2 Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: growth factors; hypertension; signal transduction; vascular smooth muscle