Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway

Exp Eye Res. 2007 May;84(5):886-93. doi: 10.1016/j.exer.2007.01.009. Epub 2007 Jan 27.

Abstract

Fenofibrate, a widely used hypolipidemic drug, has anti-inflammatory and anti-atherosclerotic effects in the vessel wall. In the present study, we report an anti-apoptotic property of fenofibrate in human retinal endothelial cells (HRECs) and describe an underlying molecular mechanism. Treatment with fenofibrate protected HRECs from apoptosis in response to serum deprivation in a dose-dependent manner. This inhibition of apoptosis by fenofibrate was not altered by peroxisome proliferator-activated receptor alpha (PPARalpha) antagonist MK 886, and selective agonist for PPARalpha, WY-14643 had no beneficial effects on serum deprivation-induced cell death. Fenofibrate potently induced a sustained activation of AMP-activated protein kinase (AMPK) and vascular endothelial growth factor (VEGF) mRNA expression. Furthermore, compound C, a specific AMPK inhibitor, almost completely blocked the fenofibrate-induced survival effect as well as VEGF mRNA expression. Taken together, these results suggest that fenofibrate prevents apoptotic cell death induced by serum deprivation through PPARalpha-independent, but AMPK-dependent pathway. Thus fenofibrate may have a novel therapeutic property that can control unwanted cell death found in diabetic retinopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Enzyme Activation / drug effects
  • Fenofibrate / pharmacology*
  • Humans
  • Hypolipidemic Agents / pharmacology*
  • Multienzyme Complexes / physiology*
  • PPAR alpha / physiology
  • Protein-Serine-Threonine Kinases / physiology*
  • Retinal Vessels / cytology
  • Retinal Vessels / drug effects*
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Hypolipidemic Agents
  • Multienzyme Complexes
  • PPAR alpha
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Fenofibrate