Aldosterone Enhances IGF-I-Mediated Signaling and Biological Function in Vascular Smooth Muscle Cells

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)