Activation of protease calpain by oxidized and glycated LDL increases the degradation of endothelial nitric oxide synthase

Yunzhou Dong, Yong Wu, Mingyuan Wu, Shuangxi Wang, Junhua Zhang, Zhonglin Xie, Jian Xu, Ping Song, Kenneth Wilson, Zhengxing Zhao, Timothy Lyons, Ming-Hui Zou

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

Oxidation and glycation of low-density lipoprotein (LDL) promote vascular injury in diabetes; however, the mechanisms underlying this effect remain poorly defined. The present study was conducted to determine the effects of 'heavily oxidized' glycated LDL (HOG-LDL) on endothelial nitric oxide synthase (eNOS) function. Exposure of bovine aortic endothelial cells with HOG-LDL reduced eNOS protein levels in a concentration- and time-dependent manner, without altering eNOS mRNA levels. Reduced eNOS protein levels were accompanied by an increase in intracellular Ca(2+), augmented production of reactive oxygen species (ROS) and induction of Ca(2+)-dependent calpain activity. Neither eNOS reduction nor any of these other effects were observed in cells exposed to native LDL. Reduction of intracellular Ca(2+) levels abolished eNOS reduction by HOG-LDL, as did pharmacological or genetic through calcium channel blockers or calcium chelator BAPTA or inhibition of NAD(P)H oxidase (with apocynin) or inhibition of calpain (calpain 1-specific siRNA). Consistent with these results, HOG-LDL impaired acetylcholine-induced endothelium-dependent vasorelaxation of isolated mouse aortas, and pharmacological inhibition of calpain prevented this effect. HOG-LDL may impair endothelial function by inducing calpain-mediated eNOS degradation in a ROS- and Ca(2+)-dependent manner.
Original languageEnglish
Pages (from-to)2899-910
Number of pages12
JournalJournal of Cellular and Molecular Medicine
Volume13
Issue number9A
DOIs
Publication statusPublished - Sep 2009

Keywords

  • Animals
  • Calcium
  • Calpain
  • Cattle
  • Cytoplasm
  • Enzyme Activation
  • Humans
  • Intracellular Space
  • Lipoproteins, LDL
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidase
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • Protease Inhibitors
  • Proteasome Endopeptidase Complex
  • Protein Processing, Post-Translational
  • Protein Transport
  • Reactive Oxygen Species
  • Time Factors
  • Transcription, Genetic

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