期刊
AMERICAN JOURNAL OF HYPERTENSION
卷 24, 期 10, 页码 1149-1155出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ajh.2011.114
关键词
angiotensin II; blood pressure; hypertension; insulin resistance; oxidative stress; signal transduction; vascular smooth muscle cell
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [20590253, 22790792]
- Sanju Alumni Research Grant
- Grants-in-Aid for Scientific Research [22790792] Funding Source: KAKEN
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 11, p38MAP kinase, and JNK were further activated by insulin. Treatment of a p38MAP kinase inhibitor, SB203580 (10 mu mol/l), and a JNK inhibitor, SP600125 (20 mu mol/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 mu mol/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.
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