title: High sodium augments angiotensin II-induced vascular smooth muscle cell proliferation through the ERK 1/2-dependent pathway.
abstract: Angiotensin II (Ang II)-induced vascular injury is exacerbated by high-salt diets. This study examined the effects of high-sodium level on Ang II-induced cell proliferation in rat vascular smooth muscle cells (VSMCs). The cells were cultured in a standard medium containing 137.5 mmol l(-1) of sodium. The high-sodium medium (140 mmol l(-1)) contained additional sodium chloride. Extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was determined by western blot analysis. Cell proliferation was evaluated by [(3)H]-thymidine incorporation. Ang II (100 nmol l(-1)) significantly increased ERK 1/2 phosphorylation and cell proliferation in the both medium containing standard sodium and high sodium. High-sodium level augmented Ang II-induced ERK 1/2 phosphorylation and cell proliferation compared with standard sodium. Pre-treatment with candesartan (1 μmol l(-1), Ang II type 1 receptor blocker) or PD98095 (10 μmol l(-1), ERK kinase iinhibitor) abolished the proliferative effect induced by high sodium/Ang II. Pre-treatment with 5-N,N-hexamethylene amiloride (30 μmol l(-1), Na(+)/H(+) exchanger type 1 (NHE-1) inhibitor), but not SN-6 (10 μmol l(-1), Na(+)/Ca(2+) exchanger inhibitor) or ouabain (1 mmol l(-1), Na(+)/K(+)-ATPase inhibitor) attenuated ERK 1/2 phosphorylation or cell proliferation. Osmotic pressure or chloride had no effect on Ang II-induced proliferative changes. High-sodium level did not affect Ang II receptor expression. Ang II increased intracellular pH via NHE-1 activation, and high-sodium level augmented the pH increase induced by Ang II. These data suggest that high-sodium level directly augments Ang II-induced VSMC proliferation through NHE-1- and ERK 1/2-dependent pathways and may offer new insights into the mechanisms of vascular remodeling by high-sodium/Ang II.
authors.affiliation: 1] Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan [2] Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Asadur
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iwamoto
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D050197:Atherosclerosis / Q000139:chemically induced / Q000473:pathology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000494:pharmacology; D003470:Culture Media; D006863:Hydrogen-Ion Concentration; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D009994:Osmolar Concentration; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D012964:Sodium / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013936:Thymidine / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D002712:Chlorides; D003470:Culture Media; D044140:Receptor, Angiotensin, Type 1; D015222:Sodium Channels; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D012964:Sodium; D013936:Thymidine
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