title: Oxidant stress in mitochondrial DNA damage, autophagy and inflammation in atherosclerosis.
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.
authors: Central Arkansas Veterans Healthcare System and the Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors: Zufeng
authors: Z
authors: Ding
authors: Shijie
authors: S
authors: Liu
authors: Xianwei
authors: X
authors: Wang
authors: Magomed
authors: M
authors: Khaidakov
authors: Yao
authors: Y
authors: Dai
authors: Jawahar L
authors: JL
authors: Mehta
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D059305:Diet, High-Fat; D004706:Endodeoxyribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D004272:DNA, Mitochondrial; D004706:Endodeoxyribonucleases; D017493:Leukocyte Common Antigens; D008077:Lipoproteins, LDL; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; D051127:Scavenger Receptors, Class E; D051217:Toll-Like Receptor 9; C115010:Becn1 protein, mouse; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C480860:Map1lc3b protein, mouse; C495138:Olr1 protein, mouse; C099252:oxidized low density lipoprotein; C019329:deoxyribonuclease II