title: Angiotensin II shifts insulin signaling into vascular remodeling from glucose metabolism in vascular smooth muscle cells.
abstract: BACKGROUND
  To clarify the role of angiotensin II (Ang II) in insulin-induced arteriosclerosis, we examined the effects of Ang II on insulin-induced mitogen-activated protein (MAP) kinase activation and cellular hypertrophy in rat vascular smooth muscle cells (VSMCs).
  
  
  METHODS
  Phosphorylated MAP kinases were detected with western blot analysis. Cellular hypertrophy and glucose uptake were evaluated from incorporation of [(3)H]-labeled-leucine and -deoxy-D-glucose, respectively. Cell sizes were measured by Coulter counter.
  
  
  RESULTS
  While Ang II (100 nmol/l, 18 h) augmented cellular hypertrophy by insulin (10 nmol/l, 24 h), insulin alone did not affect hypertrophy without Ang II pretreatment. Insulin increased p38MAP kinase and c-Jun N-terminal kinase (JNK) phosphorylation; in the presence of Ang II, p38MAP kinase, and JNK were further activated by insulin. Treatment of a p38MAP kinase inhibitor, SB203580 (10 µmol/l), and a JNK inhibitor, SP600125 (20 µmol/l), abrogated the [(3)H]-leucine incorporation by insulin in the presence of Ang II. Both the Ang II receptor blocker, RNH-6270 (100 nmol/l), and an antioxidant, ebselen (40 µmol/l), inhibited vascular cell hypertrophy. Specific depletion of insulin receptor substrate-1 with small interfering RNA increased [(3)H]-leucine incorporation by insulin (10 nmol/l, 24 h); pretreatment with Ang II attenuated insulin (10 nmol/l, 30 min)-induced glucose uptake.
  
  
  CONCLUSIONS
  Ang II attenuates insulin-stimulated glucose uptake and enhances vascular cell hypertrophy via oxidative stress- and MAP kinase-mediated pathways in VSMCs. Ang II may also cause insulin signaling to diverge from glucose metabolism into vascular remodeling, affecting insulin-induced arteriosclerosis in hypertension.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan. hitomi@kms.ac.jp
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kaifu
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fujita
authors.forename: Tadashi
authors.initials: T
authors.lastname: Sofue
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.forename: Kumiko
authors.initials: K
authors.lastname: Moriwaki
authors.forename: Taiga
authors.initials: T
authors.lastname: Hara
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Kiyomoto
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D006984:Hypertrophy; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000502:physiology; D007333:Insulin Resistance; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D000804:Angiotensin II; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose