FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis

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Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice
11:10

Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice

Published on: November 16, 2011

Kyoichiro Tsuchiya1, Jun Tanaka, Yu Shuiqing

  • 1Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.

Cell Metabolism
|March 13, 2012
PubMed

Insights

In insulin-resistant diabetes, deleting the FoxO gene in endothelial cells prevents atherosclerosis by reversing key disease pathways. This surprising finding offers potential therapeutic benefits for cardiovascular disease.

Area of Science:

  • Cardiovascular Biology
  • Endocrinology
  • Molecular Biology

Background:

  • Atherosclerotic cardiovascular disease is a major cause of mortality in type 2 diabetes.
  • Endothelial dysfunction, characterized by impaired nitric oxide bioavailability and inflammation, drives atherosclerosis.
  • Insulin resistance exacerbates vascular complications.

Purpose of the Study:

  • To investigate the role of transcription factor FoxO in endothelial cells in the development of atherosclerosis in the context of insulin resistance.
  • To determine if inhibiting FoxO in endothelial cells can prevent or reverse atherosclerosis-related vascular dysfunction.
  • To elucidate the molecular mechanisms underlying the effects of FoxO on endothelial cell function and atherosclerosis.

Main Methods:

  • Utilized low-density lipoprotein receptor knockout (Ldlr-/-) mice, a model for atherosclerosis.
  • Generated endothelial cell-specific FoxO isoform knockout mice.
  • Assessed atherosclerotic lesion development and vascular function.
  • Analyzed molecular pathways including nitric oxide availability, inflammation, superoxide generation, and insulin signaling (Akt, Irs1, Irs2).

Main Results:

  • Ablation of FoxO isoforms in endothelial cells significantly prevented atherosclerosis in Ldlr-/- mice.
  • FoxO deletion reversed key atherogenic subphenotypes, including improved nitric oxide availability, reduced inflammation, and decreased superoxide generation.
  • Paradoxically, FoxO deletion led to decreased insulin-dependent Akt phosphorylation due to reduced expression of insulin receptor substrates (Irs1 and Irs2).
  • FoxO appears to be a shared effector of atherogenic pathways in endothelial cells.

Conclusions:

  • FoxO transcription factors in endothelial cells are critical mediators of atherosclerosis in insulin-resistant diabetes.
  • Inhibition of FoxO in endothelial cells demonstrates atheroprotective effects by modulating multiple detrimental pathways.
  • Targeting FoxO in endothelial cells represents a potential therapeutic strategy for managing diabetes-associated cardiovascular disease.

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