on October 9, 2003
Published online before print October 9, 2003, doi: 10.1161/01.ATV.0000099788.31333.DB
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Submitted on September 3, 2003
Accepted on September 25, 2003
Insulin-Like Growth Factor-1 Receptor Activation Inhibits Oxidized LDL-Induced Cytochrome C Release and Apoptosis via the Phosphatidylinositol 3 Kinase/Akt Signaling Pathway
Yangxin Li ;
From the Tulane University Medical Center, New Orleans, La; Teikyo University, Kanagawa, Japan; and The University of Texas Medical Branch, Galveston, Tex.
* To whom correspondence should be addressed. E-mail: pdelafon{at}tulane.edu.
Objective--We have shown previously that oxidized LDL decreases insulin-like growth factor-1 (IGF-1) and IGF-1 receptor expression in vascular smooth muscle cells and that IGF-1 and IGF-1 receptor expression are reduced in the deep intima of early atherosclerotic lesions. Because oxidized LDL is potentially important for the depletion of vascular smooth muscle cells contributing to plaque destabilization, we studied the role of IGF-1 in oxidized LDL-induced apoptosis.
Methods and Results--We provide evidence that oxidized LDL-induced apoptosis is caused by decreased mitochondrial membrane potential and increased cytochrome C release in human aortic vascular smooth muscle cells. Overexpression of the IGF-1 receptor by using an adenovirus completely abrogated these effects. The antiapoptotic function of the IGF-1 receptor was associated with increased Akt kinase activity and increased expression of phosphorylated Bad. Moreover, a dominant-negative p85 phosphatidylinositol 3-kinase adenovirus blocked the capacity of the IGF-1 receptor to prevent oxidized LDL-induced apoptosis.
Conclusions--Our data demonstrate that IGF-1 receptor activation inhibits oxidized LDL-induced cytochrome C release and apoptosis through the phosphatidylinositol 3-kinase/Akt signaling pathway and suggest that genetic or pharmacological activation of the IGF-1 receptor may be a useful strategy to stabilize atherosclerotic plaques.
Key words: vascular smooth muscle cells • atherosclerosis • growth factors • signal transduction • receptors
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