PPARalpha activators upregulate eNOS activity and inhibit cytokine-induced NF-kappaB activation through AMP-activated protein kinase activation

Life Sci. 2008 Apr 9;82(15-16):884-91. doi: 10.1016/j.lfs.2008.02.002. Epub 2008 Feb 16.


Endothelium-derived NO is an important mediator of vascular protection and adhesion molecule expression on the endothelial cell surface is critical for leukocyte recruitment to atherosclerotic lesions. We hypothesized that AMP-activated protein kinase (AMPK) activity is a down-stream mediator of the beneficial effects of PPARalpha activators on vascular endothelial cells. Treatment of human umbilical vein endothelial cells (HUVEC) with fenofibrate or WY14643 resulted in transient activation of AMPK, as monitored by phosphorylation of AMPK and its down-stream target, acetyl-CoA carboxylase. Fenofibrate caused phosphorylation of Akt and eNOS, leading to increased production of NO, and also caused inhibition of cytokine-induced NF-kappaB activation, leading to suppression of expression of adhesion molecule genes. Significant decreases in eNOS activity and NO production in response to fenofibrate were observed in cells treated with AMPK siRNA or with AraA, a pharmacological inhibitor of AMPK. The attenuation of fenofibrate-induced inhibition of NF-kappaB activation was observed in mouse endothelial (SVEC4) cells treated with AMPK siRNA or with AraA. We demonstrated that TNFalpha stimulates IkappaB-alpha phosphorylation through induction of IKK activity, and that fenofibrate inhibits IKK activity and TNFalpha-induced IkappaB-alpha phosphorylation. Our findings suggest that the beneficial effects of PPARalpha activators on endothelial cells such as inhibition of diabetic microangiopathy might be attributed to the induction of AMPK activation beyond its lipid-lowering actions.

MeSH terms

  • Biotransformation / drug effects
  • Blotting, Western
  • Cell Line
  • Cyclic AMP-Dependent Protein Kinases / physiology*
  • Cytokines / antagonists & inhibitors*
  • Cytokines / pharmacology
  • E-Selectin / biosynthesis
  • E-Selectin / genetics
  • Fenofibrate / pharmacology
  • Humans
  • Hypolipidemic Agents / pharmacology
  • I-kappa B Kinase / metabolism
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase Type III / biosynthesis*
  • PPAR alpha / agonists*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation / drug effects
  • Vascular Cell Adhesion Molecule-1 / biosynthesis
  • Vascular Cell Adhesion Molecule-1 / genetics


  • Cytokines
  • E-Selectin
  • Hypolipidemic Agents
  • NF-kappa B
  • PPAR alpha
  • RNA, Messenger
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • I-kappa B Kinase
  • Cyclic AMP-Dependent Protein Kinases
  • Fenofibrate