Aldosterone Enhances IGF-I-Mediated Signaling and Biological Function in Vascular Smooth Muscle Cells
Aldosterone Enhances IGF-I-Mediated Signaling and Biological Function in Vascular Smooth Muscle Cells
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DOI：
10.1210/en.2010-0350
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发表时间：
2010-12-01
期刊：
影响因子：
4.8
通讯作者：
Clemmons, David R.
中科院分区：
文献类型：
--
作者：
Cascella, Teresa;Radhakrishnan, Yashwanth;Clemmons, David R.
IGF-I途径和肾素-血管紧张素-醛固酮轴均参与高血压和动脉粥样硬化的发病机制，但尚无关于IGF-I和醛固酮相互作用或其在血管平滑肌细胞（VSMC）中潜在协同作用的信息。本研究的目的是调查醛固酮是否影响 IGF-I 信号传导，并确定醛固酮影响 IGF-I 功能的机制。醛固酮导致 Akt（1.87 +/- 0.24，P < 0.001）、MAPK（1.78 +/- 0.13，P < 0.001）、p70S6 激酶（1.92 +/- 0.15，P < 0.001）、IGF-I 受体（1.69 +/- 0.05，P < 0.01）、与单独的 IGF-I 治疗相比，IGF-I 的磷酸化反应（1.7 +/- 0.04，P < 0.01）（倍数增加，平均值 +/- SEM，n = 3）。 VSMC 增殖、迁移和蛋白质合成也显着增加（与单独使用 IGF-I 相比，分别增加 1.63 +/- 0.03、1.56 +/- 0.08 和 1.51 +/- 0.04 倍，n = 3，P < 0.001）。醛固酮诱导骨桥蛋白 (OPN) mRNA 表达和 αVβ3-整合素激活以及 IGF-I 受体合成增加。醛固酮的增强作用被依普利酮 (10 μmol/L)、放线菌素-D (20 nmol/L) 和阻断 OPN 结合的抗 α V β 3 整合素抗体抑制。抗氧化剂 N-乙酰半胱氨酸（2 mmol/升）完全抑制醛固酮诱导这些变化的能力。总之，我们的结果表明，醛固酮通过诱导 OPN、随后激活 αVβ3-整合素并增加 IGF-I 受体，增强 VSMC 中的 IGF-I 信号传导和生物作用。这些变化部分是通过氧化应激增加介导的。这些发现提出了醛固酮加速动脉粥样硬化发展的新机制。 （内分泌学151：5851-5864，2010）
The IGF-I pathway and renin-angiotensin-aldosterone axis are both involved in the pathogenesis of hypertension and atherosclerosis, but no information is available about IGF-I and aldosterone interaction or their potential synergistic effects in vascular smooth muscle cells (VSMCs). The aims of this study were to investigate whether aldosterone influences IGF-I signaling and to determine the mechanism( s) by which aldosterone affects IGF-I function. Aldosterone resulted in significant increases in the Akt (1.87 +/- 0.24, P < 0.001), MAPK (1.78 +/- 0.13, P < 0.001), p70S6kinase (1.92 +/- 0.15, P < 0.001), IGF-I receptor (1.69 +/- 0.05, P < 0.01), and insulin receptor substrate-1 (1.7 +/- 0.04, P < 0.01) (fold increase, mean +/- SEM, n = 3) phosphorylation responses to IGF-I compared with IGF-I treatment alone. There were also significant increases in VSMC proliferation, migration, and protein synthesis (1.63 +/- 0.03-, 1.56 +/- 0.08-, and 1.51 +/- 0.04-fold increases compared with IGF-I alone, respectively, n = 3, P < 0.001). Aldosterone induced osteopontin (OPN) mRNA expression and activation of alpha V beta 3-integrin as well as an increase in the synthesis of IGF-I receptor. The enhancing effects of aldosterone were inhibited by eplerenone (10 mu mol/liter), actinomycin-D (20 nmol/liter), and an anti-alpha V beta 3-integrin antibody that blocks OPN binding. The antioxidant N-acetylcysteine (2 mmol/liter) completely inhibited the ability of aldosterone to induce any of these changes. In conclusion, our results show that aldosterone enhances IGF-I signaling and biological actions in VSMCs through induction of OPN followed by its subsequent activation of the alpha V beta 3-integrin and by increasing IGF-I receptor. These changes are mediated in part through increased oxidative stress. The findings suggest a new mechanism by which aldosterone could accelerate the development of atherosclerosis. (Endocrinology 151: 5851-5864, 2010)