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Caveolin-1 Down-Regulation Inhibits Insulin-Like Growth Factor-I Receptor Signal Transduction in H9C2 Rat Cardiomyoblasts

Departments of Endocrinology and Medicine (B.S., L.B., R.C., D.M.) and Internal Medicine (S.G.), University of Genova, 5-16132 Genova, Italy

Address all correspondence and requests for reprints to: Davide Maggi, M.D., Ph.D., Department of Endocrinology and Medicine, Viale Benedetto XV, 6, University of Genova, 5-16132 Genova, Italy. E-mail: davide.maggi{at}unige.it.

Caveolin (Cav)-1, the major caveolar protein, directly interacts with IGF-I receptor (IGF-IR) and its intracellular substrates. To determine the role of Cav-1 in IGF-IR signaling, we transfected H9C2 cells with small interfering RNA specific for Cav-1-siRNA. The selective down-regulation of Cav-1 (90%) was associated with a smaller reduction of Cav-2, whereas Cav-3 expression was unaffected. A significant reduction of IGF-IR tyrosine phosphorylation in Cav-1-siRNA H9C2 cells was found compared with H9C2 control cells (Ctr-siRNA). The reduced IGF-IR autophosphorylation resulted in a decrease of insulin receptor substrate-1, Shc, and Akt activation. In addition, in Cav-1-siRNA H9C2 cells, IGF-I did not prevent apoptosis, suggesting that Cav-1 is required to mediate the antiapoptotic effect of IGF-I in cardiomyoblasts. The down-regulation of Cav-1 decreased IGF-IR activation and affected the ability of IGF-I to prevent apoptosis after serum withdrawal also in human umbilical vein endothelial cells. These results demonstrate that: 1) Cav-1 down-regulation negatively affects IGF-IR tyrosine phosphorylation; 2) this effect causes a reduced activation of insulin receptor substrate-1, Shc, and Akt; and 3) Cav-1 is involved in IGF-IR antiapoptotic signaling after serum deprivation.