Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 32, Issue 2, Pages 257-U193Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.111.240697
Keywords
insulin resistance; reactive oxygen species; receptors; signal transduction; aldosterone
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [20590253, 22790792]
- Grants-in-Aid for Scientific Research [22790792] Funding Source: KAKEN
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Objective-We previously showed that aldosterone induces insulin resistance in rat vascular smooth muscle cells (VSMCs). Because insulin-like growth factor-1 receptor (IGF1R) affects insulin signaling, we hypothesized that aldosterone induces vascular insulin resistance and remodeling via upregulation of IGF1R and its hybrid insulin/insulin-like growth factor-1 receptor. Methods and Results-Hybrid receptor expression was measured by immunoprecipitation. Hypertrophy of VSMCs was evaluated by H-3-labeled leucine incorporation. Aldosterone (10 nmol/L) significantly increased protein and mRNA expression of IGF1R and hybrid receptor in VSMCs but did not affect insulin receptor expression. Mineralocorticoid receptor blockade with eplerenone inhibited aldosterone-induced increases in IGF1R and hybrid receptor. Aldosterone augmented insulin (100 nmol/L)-induced extracellular signal-regulated kinase 1/2 phosphorylation. Insulin-induced leucine incorporation and alpha-smooth muscle actin expression were also augmented by aldosterone in VSMCs. These aldosterone-induced changes were significantly attenuated by eplerenone or picropodophyllin, an IGF1R inhibitor. Chronic infusion of aldosterone (0.75 mu g/hour) increased blood pressure and aggravated glucose metabolism in rats. Expression of hybrid receptor, azan-positive area, and oxidative stress in aorta was increased in aldosterone-infused rats. Spironolactone and tempol prevented these aldosterone-induced changes. Conclusion-Aldosterone induces vascular remodeling through IGF1R- and hybrid receptor-dependent vascular insulin resistance. Mineralocorticoid receptor blockade may attenuate angiopathy in hypertensive patients with hyperinsulinemia. (Arterioscler Thromb Vasc Biol. 2012;32:257-263.)
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