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A redox-sensitive pathway mediates oxidized LDL-induced downregulation of insulin-like growth factor-1 receptor

Yusuke Higashi1, Tao Peng, Jie Du

  • 1Section of Cardiology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.

Journal of Lipid Research
|April 5, 2005
PubMed

Insights

Oxidized low-density lipoprotein (OxLDL) induces apoptosis by downregulating the insulin-like growth factor-1 receptor (IGF-1R) through reactive oxygen species (ROS) production, potentially via lipoxygenase and CD36 pathways.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Oxidative Stress

Background:

  • Oxidized low-density lipoprotein (OxLDL) promotes atherosclerosis, partly by inducing apoptosis in vascular cells.
  • OxLDL downregulates insulin-like growth factor-1 receptor (IGF-1R), and IGF-1R overexpression protects against OxLDL-induced apoptosis.

Purpose of the Study:

  • To investigate the signaling pathways by which OxLDL downregulates IGF-1R and induces apoptosis in human aortic smooth muscle cells.
  • To identify the role of reactive oxygen species (ROS) and specific signaling molecules in these OxLDL effects.

Main Methods:

  • Inhibition of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways.
  • Treatment with antioxidants (catalase, superoxide dismutase, Trolox) and lipoxygenase inhibitors (nordihydroguaiaretic acid, AA-861, baicalein).
  • Assessment of IGF-1R expression, apoptosis, and ROS production; use of anti-CD36 antibody.

Main Results:

  • Inhibition of ERK, p38 MAPK, and PPARγ pathways did not prevent OxLDL-induced IGF-1R downregulation or apoptosis.
  • Antioxidants and lipoxygenase inhibitors blocked OxLDL-induced IGF-1R downregulation, apoptosis, and ROS production.
  • Anti-CD36 antibody significantly inhibited OxLDL-induced IGF-1R downregulation, apoptosis, and ROS production.

Conclusions:

  • OxLDL downregulates IGF-1R and induces apoptosis via redox-sensitive pathways, distinct from MAPK and PPARγ signaling.
  • Lipoxygenase activity and ROS production appear critical in mediating these OxLDL effects.
  • A CD36-dependent mechanism may be involved in OxLDL-induced IGF-1R downregulation and apoptosis.

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