Journal Article

Angiotensin II Shifts Insulin Signaling Into Vascular Remodeling From Glucose Metabolism in Vascular Smooth Muscle Cells

Hirofumi Hitomi, Kumiko Kaifu, Yoshiko Fujita, Tadashi Sofue, Daisuke Nakano, Kumiko Moriwaki, Taiga Hara, Hideyasu Kiyomoto, Masakazu Kohno, Hiroyuki Kobori and Akira Nishiyama

in American Journal of Hypertension

Published on behalf of American Journal of Hypertension, Ltd.

Volume 24, issue 10, pages 1149-1155
Published in print October 2011 | ISSN: 0895-7061
Published online October 2011 | e-ISSN: 1941-7225 | DOI: http://dx.doi.org/10.1038/ajh.2011.114
Angiotensin II Shifts Insulin Signaling Into Vascular Remodeling From Glucose Metabolism in Vascular Smooth Muscle Cells

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  • Neuroendocrinology and Autonomic Nervous System
  • Biochemistry
  • Endocrinology and Diabetes

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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 [3H]-labeled-leucine and -deoxy-D-glucose, respectively. Cell sizes were measured by Coulter counter.

Results

While Ang II (100nmol/l, 18h) augmented cellular hypertrophy by insulin (10nmol/l, 24h), 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 (10µmol/l), and a JNK inhibitor, SP600125 (20µmol/l), abrogated the [3H]-leucine incorporation by insulin in the presence of Ang II. Both the Ang II receptor blocker, RNH-6270 (100nmol/l), and an antioxidant, ebselen (40µmol/l), inhibited vascular cell hypertrophy. Specific depletion of insulin receptor substrate-1 with small interfering RNA increased [3H]-leucine incorporation by insulin (10nmol/l, 24h); pretreatment with Ang II attenuated insulin (10nmol/l, 30min)-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.

American Journal of Hypertension advance online publication 30 June 2011; doi:10.1038/ajh.2011.114

Keywords: angiotensin II; blood pressure; hypertension; insulin resistance; oxidative stress; signal transduction; vascular smooth muscle cell

Journal Article.  3698 words.  Illustrated.

Subjects: Neuroendocrinology and Autonomic Nervous System ; Biochemistry ; Endocrinology and Diabetes

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