期刊
EXPERIMENTAL CELL RESEARCH
卷 317, 期 17, 页码 2420-2428出版社
ELSEVIER INC
DOI: 10.1016/j.yexcr.2011.07.016
关键词
Insulin resistance; Signal transduction; Mechanical stretch; Vascular smooth muscle cell; Insulin-like growth factor-1 receptor
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [20590253]
- Japan Research Foundation for Clinical Pharmacology
- Kagawa University
- Grants-in-Aid for Scientific Research [20590253, 22790792] Funding Source: KAKEN
Insulin resistance and hypertension have been implicated in the pathogenesis of cardiovascular disease; however, little is known about the roles of insulin and mechanical force in vascular smooth muscle cell (VSMC) remodeling. We investigated the contribution of mechanical stretch to insulin-induced VSMC proliferation. Thymidine incorporation was stimulated by insulin in stretched VSMCs, but not in un-stretched VSMCs. Insulin increased 2-deoxy-glucose incorporation in both stretched and un-stretched VSMCs. Mechanical stretch augmented insulin-induced extracellular signal-regulated kinase (ERK) and Akt phosphorylation. Inhibitors of epidermal growth factor (EGF) receptor tyrosine kinase and Src attenuated insulin-induced ERK and Akt phosphorylation, as well as thymidine incorporation, whereas 2-deoxy-glucose incorporation was not affected by these inhibitors. Moreover, stretch augmented insulin-like growth factor (IGF)-1 receptor expression, although it did not alter the expression of insulin receptor and insulin receptor substrate-1. Insulin-induced ERK and Akt activation, and thymidine incorporation were inhibited by siRNA for the IGF-1 receptor. Mechanical stretch augments insulin-induced VSMC proliferation via upregulation of IGF-1 receptor, and downstream Src/EGF receptor-mediated ERK and Akt activation. Similar to in vitro experiment, IGF-1 receptor expression was also augmented in hypertensive rats. These results provide a basis for clarifying the molecular mechanisms of vascular remodeling in hypertensive patients with hyperinsulinemia. (C) 2011 Elsevier Inc. All rights reserved.
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