High-density lipoprotein nitration and chlorination catalyzed by myeloperoxidase impair its effect of promoting endothelial repair

Free Radic Biol Med. 2013 Jul;60:272-81. doi: 10.1016/j.freeradbiomed.2013.02.004. Epub 2013 Feb 14.

Abstract

High-density lipoprotein (HDL) plays a key role in protecting against atherosclerosis. In cardiovascular disease, HDL can be nitrated and chlorinated by myeloperoxidase (MPO). In this study, we discovered that MPO-oxidized HDL is dysfunctional in promoting endothelial repair compared to normal HDL. Proliferation assay, wound healing, and transwell migration experiments showed that MPO-oxidized HDL was associated with a reduced stimulation of endothelial cell (EC) proliferation and migration. In addition, we found that Akt and ERK1/2 phosphorylation in ECs was significantly lower when ECs were incubated with oxidized HDL compared with normal HDL. To further determine whether oxidized HDL diminished EC migration through the PI3K/Akt and MEK/ERK pathways, we performed experiments with inhibitors of both these pathways. The transwell experiments performed in the presence of these inhibitors showed that the migration capacity was reduced and the differences observed between normal HDL and oxidized HDL were diminished. Furthermore, to study the effects of oxidized HDL on endothelial cells in vivo, we performed a carotid artery electric injury model on nude mice injected with either normal or oxidized HDL. Oxidized HDL inhibited reendothelialization compared to normal HDL in vivo. These findings implicate a key role for MPO-oxidized HDL in the pathogenesis of cardiovascular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiovascular Diseases / metabolism*
  • Cardiovascular Diseases / physiopathology
  • Catalysis
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelium / growth & development*
  • Endothelium / metabolism
  • Halogenation
  • Humans
  • Lipoproteins, HDL / administration & dosage*
  • Lipoproteins, HDL / chemistry
  • Lipoproteins, HDL / metabolism
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Nitrates / administration & dosage
  • Nitrates / chemistry
  • Nitrates / metabolism
  • Oxidation-Reduction
  • Peroxidase / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism

Substances

  • Lipoproteins, HDL
  • Nitrates
  • Peroxidase
  • Proto-Oncogene Proteins c-akt