Oxidant stress in mitochondrial DNA damage, autophagy and inflammation in atherosclerosis

Sci Rep. 2013;3:1077. doi: 10.1038/srep01077. Epub 2013 Jan 16.

Abstract

Our studies in HUVECs show that ox-LDL induced autophagy and damaged mtDNA leading to TLR9 expression. LOX-1 antibody or the ROS inhibitor apocynin attenuated ox-LDL-mediated autophagy, mtDNA damage and TLR9 expression, suggesting that these events are LOX-1 and ROS-dependent phenomena. Experiments using siRNA to DNase II indicated that DNase II digests mtDNA to protect the tissue from inflammation. Next, we studied and found intense autophagy, TLR9 expression and inflammatory signals (CD45 and CD68) in the aortas of LDLR knockout mice fed high cholesterol diet. Deletion of LOX-1 (LDLR/LOX-1 double knockout mice) attenuated autophagy, TLR9 expression as well as CD45 and CD68. Damaged mtDNA signal was also very high in LDLR knockout mice aortas, and this signal was attenuated by LOX-1 deletion. Thus, it appears that oxidative stress-mediated damaged mtDNA that escapes autophagy induces a potent inflammatory response in atherosclerosis.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Apoptosis Regulatory Proteins / metabolism
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Autophagy / drug effects*
  • Beclin-1
  • Cells, Cultured
  • DNA Damage / drug effects*
  • DNA, Mitochondrial / metabolism*
  • Diet, High-Fat
  • Endodeoxyribonucleases / antagonists & inhibitors
  • Endodeoxyribonucleases / genetics
  • Endodeoxyribonucleases / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Inflammation / metabolism
  • Leukocyte Common Antigens / metabolism
  • Lipoproteins, LDL / pharmacology*
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / metabolism
  • Oxidative Stress / drug effects*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Scavenger Receptors, Class E / deficiency
  • Scavenger Receptors, Class E / genetics
  • Scavenger Receptors, Class E / metabolism
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / metabolism

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, mouse
  • CD68 antigen, human
  • DNA, Mitochondrial
  • Lipoproteins, LDL
  • MAP1LC3 protein, mouse
  • Microtubule-Associated Proteins
  • Olr1 protein, mouse
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Receptors, LDL
  • Scavenger Receptors, Class E
  • Toll-Like Receptor 9
  • oxidized low density lipoprotein
  • Endodeoxyribonucleases
  • deoxyribonuclease II
  • Leukocyte Common Antigens