Published online before print October 9, 2003, doi: 10.1161/01.ATV.0000099788.31333.DB
© 2003 American Heart Association, Inc.
Vascular Biology |
Insulin-Like Growth Factor-1 Receptor Activation Inhibits Oxidized LDL-Induced Cytochrome C Release and Apoptosis via the Phosphatidylinositol 3 Kinase/Akt Signaling Pathway
From the Tulane University Medical Center, New Orleans, LA; Teikyo University, Kanagawa, Japan; and The University of Texas Medical Branch, Galveston, TX.
Correspondence to Patrice Delafontaine, MD, FACC, FAHA, FACP, FESC, Tulane University Medical Center, School of Medicine, Section of Cardiology, 1430 Tulane Avenue, New Orleans, LA 70112–2699. 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
This article has been cited by other articles:
 |
|
 |
|
  J. S. Titterington, S. Sukhanov, Y. Higashi, C. Vaughn, C. Bowers, and P. Delafontaine Growth Hormone-Releasing Peptide-2 Suppresses Vascular Oxidative Stress in ApoE-/- Mice But Does Not Reduce Atherosclerosis Endocrinology, December 1, 2009; 150(12): 5478 - 5487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. W. Small and J. G. Pickering Nuclear Degradation of Wilms Tumor 1-associating Protein and Survivin Splice Variant Switching Underlie IGF-1-mediated Survival J. Biol. Chem., September 11, 2009; 284(37): 24684 - 24695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Higashi, S. Sukhanov, S. Parthasarathy, and P. Delafontaine The ubiquitin ligase Nedd4 mediates oxidized low-density lipoprotein-induced downregulation of insulin-like growth factor-1 receptor Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1684 - H1689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Allard, N. Figg, M. R. Bennett, and T. D. Littlewood Akt Regulates the Survival of Vascular Smooth Muscle Cells via Inhibition of FoxO3a and GSK3 J. Biol. Chem., July 11, 2008; 283(28): 19739 - 19747. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Martin, D. Gunnell, E. Whitley, A. Nicolaides, M. Griffin, N. Georgiou, G. Davey Smith, S. Ebrahim, and J. M. P. Holly Associations of Insulin-Like Growth Factor (IGF)-I, IGF-II, IGF Binding Protein (IGFBP)-2 and IGFBP-3 with Ultrasound Measures of Atherosclerosis and Plaque Stability in an Older Adult Population J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1331 - 1338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sukhanov, Y. Higashi, S.-Y. Shai, C. Vaughn, J. Mohler, Y. Li, Y.-H. Song, J. Titterington, and P. Delafontaine IGF-1 Reduces Inflammatory Responses, Suppresses Oxidative Stress, and Decreases Atherosclerosis Progression in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2684 - 2690. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sukhanov, Y. Higashi, S.-Y. Shai, H. Itabe, K. Ono, S. Parthasarathy, and P. Delafontaine Novel Effect of Oxidized Low-Density Lipoprotein: Cellular ATP Depletion via Downregulation of Glyceraldehyde-3-Phosphate Dehydrogenase Circ. Res., July 21, 2006; 99(2): 191 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, Y.-H. Song, J. Mohler, and P. Delafontaine ANG II induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2116 - H2123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Higashi, T. Peng, J. Du, S. Sukhanov, Y. Li, H. Itabe, S. Parthasarathy, and P. Delafontaine A redox-sensitive pathway mediates oxidized LDL-induced downregulation of insulin-like growth factor-1 receptor J. Lipid Res., June 1, 2005; 46(6): 1266 - 1277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Delafontaine, Y.-H. Song, and Y. Li Expression, Regulation, and Function of IGF-1, IGF-1R, and IGF-1 Binding Proteins in Blood Vessels Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 435 - 444. [Abstract] [Full Text]
|
|
|
|
|
|
N. Kume and T. Kita Apoptosis of Vascular Cells by Oxidized LDL: Involvement of Caspases and LOX-1 and Its Implication in Atherosclerotic Plaque Rupture Circ. Res., February 20, 2004; 94(3): 269 - 270. [Full Text] [PDF]
|
|