Cilostazol activates AMP-activated protein kinase and restores endothelial function in diabetes

Am J Hypertens. 2008 Apr;21(4):451-7. doi: 10.1038/ajh.2008.6. Epub 2008 Feb 7.

Abstract

Background: Endothelial dysfunction plays a key role in atherogenesis. We investigated whether AMP-activated protein kinase (AMPK) activity is a downstream mediator of the beneficial effects of cilostazol on vascular endothelial cells and whether cilostazol might reverse endothelial dysfunction in diabetic rats.

Methods and results: Treatment of human umbilical vein endothelial cells (HUVECs) with cilostazol resulted in time-dependent activation of AMPK, as monitored by phosphorylation of AMPK and its down-stream target, acetyl-CoA carboxylase (ACC). Activation of AMPK by cilostazol was through signaling pathway independent of cyclic AMP and caused phosphorylation of endothelial nitric oxide synthase (eNOS), leading to increased production of nitric oxide (NO), while inhibiting cytokine-induced nuclear factor-kappaB (NF-kappaB) activation, leading to suppression of VCAM-1 gene expression. Significantly reduced eNOS activity and NO production in response to cilostazol and attenuation of cilostazol-induced inhibition of NF-kappaB activation were observed in cells treated with AMPK siRNA. We also demonstrated that administration of cilostazol to diabetic rats significantly restored endothelium-dependent vasodilation. Furthermore, treatment of diabetic rats with cilostazol increased tetrahydrobiopterin (BH4) levels in the aorta. Thus, recovery of BH4 following administration of cilostazol might also contribute to restoration of endothelial function in diabetic rats.

Conclusions: Our findings suggest that the beneficial effects of cilostazol on endothelial function may be due to AMPK activation. Restoration of endothelial dysfunction in diabetic rats by cilostazol is at least partly attributed to amelioration of biopterin metabolism in the aorta.

Publication types

  • Comparative Study

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Aorta / physiopathology
  • Blood Glucose / metabolism
  • Blotting, Western
  • Cells, Cultured
  • Chromatography, High Pressure Liquid
  • Cilostazol
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / physiopathology
  • Disease Progression
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiopathology*
  • Gene Expression / drug effects
  • Humans
  • Male
  • Mice
  • Multienzyme Complexes / drug effects
  • Multienzyme Complexes / metabolism*
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase / drug effects
  • Nitric Oxide Synthase / metabolism
  • Phosphorylation / drug effects
  • Polymerase Chain Reaction
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / genetics
  • Rats
  • Rats, Long-Evans
  • Tetrazoles / pharmacology*
  • Umbilical Veins / metabolism
  • Umbilical Veins / pathology
  • Umbilical Veins / physiopathology
  • Vascular Cell Adhesion Molecule-1 / biosynthesis
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vasodilation / drug effects*
  • Vasodilator Agents / pharmacology*

Substances

  • Blood Glucose
  • Multienzyme Complexes
  • NF-kappa B
  • RNA, Messenger
  • Tetrazoles
  • Vascular Cell Adhesion Molecule-1
  • Vasodilator Agents
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Cilostazol