Aldosterone enhances IGF-I-mediated signaling and biological function in vascular smooth muscle cells.

Abstract

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 αVβ3-integrin as well as an increase in the synthesis of IGF-I receptor. The enhancing effects of aldosterone were inhibited by eplerenone (10 μmol/liter), actinomycin-D (20 nmol/liter), and an anti-αVβ3-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 αVβ3-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.

• Authors: Teresa Cascella, Yashwanth Radhakrishnan, Laura A Maile, Walker H Busby Jr, Katherine Gollahon, Annamaria Colao, David R Clemmons
• Journal: Endocrinology (Endocrinology) Vol. 151 Issue 12 Pg. 5851-64 (Dec 2010) ISSN: 1945-7170 [Electronic] United States
• PMID: 20881255 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Integrin alphaVbeta3
• Osteopontin
• Aldosterone
• Insulin-Like Growth Factor I
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• Mitogen-Activated Protein Kinase Kinases

Topics

• Aldosterone (pharmacology)
• Animals
• Aorta (cytology)
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Insulin-Like Growth Factor I (metabolism)
• Integrin alphaVbeta3 (genetics, metabolism)
• Mitogen-Activated Protein Kinase Kinases (genetics, metabolism)
• Muscle, Smooth, Vascular (cytology, drug effects)
• Myocytes, Smooth Muscle (drug effects, physiology)
• Osteopontin (genetics, metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa (genetics, metabolism)
• Signal Transduction (physiology)
• Swine