Abstract | BACKGROUND: METHODS AND RESULTS:
mtDNA damage occurred early in the vessel wall in apolipoprotein E-null ( ApoE(-/-)) mice, before significant atherosclerosis developed. mtDNA defects were also identified in circulating monocytes and liver and were associated with mitochondrial dysfunction. To determine whether mtDNA damage directly promotes atherosclerosis, we studied ApoE(-/-) mice deficient for mitochondrial polymerase-γ proofreading activity (polG(-/-)/ ApoE(-/-)). polG(-/-)/ ApoE(-/-) mice showed extensive mtDNA damage and defects in oxidative phosphorylation but no increase in reactive oxygen species. polG(-/-)/ ApoE(-/-) mice showed increased atherosclerosis, associated with impaired proliferation and apoptosis of vascular smooth muscle cells, and hyperlipidemia. Transplantation with polG(-/-)/ ApoE(-/-) bone marrow increased the features of plaque vulnerability, and polG(-/-)/ ApoE(-/-) monocytes showed increased apoptosis and inflammatory cytokine release. To examine mtDNA damage in human atherosclerosis, we assessed mtDNA adducts in plaques and in leukocytes from patients who had undergone virtual histology intravascular ultrasound characterization of coronary plaques. Human atherosclerotic plaques showed increased mtDNA damage compared with normal vessels; in contrast, leukocyte mtDNA damage was associated with higher-risk plaques but not plaque burden. CONCLUSIONS: We show that mtDNA damage in vessel wall and circulating cells is widespread and causative and indicates higher risk in atherosclerosis. Protection against mtDNA damage and improvement of mitochondrial function are potential areas for new therapeutics.
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Authors | Emma Yu, Patrick A Calvert, John R Mercer, James Harrison, Lauren Baker, Nichola L Figg, Sheetal Kumar, Julie C Wang, Liam A Hurst, Daniel R Obaid, Angela Logan, Nick E J West, Murray C H Clarke, Antonio Vidal-Puig, Michael P Murphy, Martin R Bennett |
Journal | Circulation
(Circulation)
Vol. 128
Issue 7
Pg. 702-12
(Aug 13 2013)
ISSN: 1524-4539 [Electronic] United States |
PMID | 23841983
(Publication Type: Journal Article)
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Chemical References |
- Apolipoproteins E
- Cytokines
- DNA Adducts
- DNA, Mitochondrial
- Reactive Oxygen Species
- DNA Polymerase gamma
- DNA-Directed DNA Polymerase
- Polg protein, mouse
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Topics |
- Adiposity
- Adult
- Aged
- Animals
- Apolipoproteins E
(genetics)
- Apoptosis
- Atherosclerosis
(etiology, genetics, metabolism, pathology)
- Cells, Cultured
- Cytokines
(metabolism)
- DNA Adducts
(analysis)
- DNA Damage
- DNA Polymerase gamma
- DNA, Mitochondrial
(chemistry)
- DNA-Directed DNA Polymerase
(deficiency, genetics)
- Electron Transport
- Female
- Humans
- Hyperlipidemias
(genetics)
- Leukocytes
(metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Middle Aged
- Mitochondria
(chemistry, pathology, physiology)
- Monocytes
(metabolism, pathology)
- Muscle, Smooth, Vascular
(metabolism, pathology)
- Myocytes, Smooth Muscle
(pathology)
- Oxygen Consumption
- Plaque, Atherosclerotic
(pathology)
- Radiation Chimera
- Reactive Oxygen Species
- Risk
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