|Title||DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome.|
|Publication Type||Journal Article|
|Year of Publication||2010|
|Authors||Mercer, JR, Cheng, K-K, Figg, N, Gorenne, I, Mahmoudi, M, Griffin, J, Vidal-Puig, A, Logan, A, Murphy, MP, Bennett, M|
|Date Published||2010 Oct 15|
|Keywords||Animals, Apolipoproteins E, Ataxia Telangiectasia Mutated Proteins, Atherosclerosis, Cell Cycle Proteins, Dietary Fats, DNA Damage, DNA, Mitochondrial, DNA-Binding Proteins, Haplotypes, Hyperlipidemias, Metabolic Syndrome X, Metabolomics, Mice, Mice, Mutant Strains, Mitochondria, Muscle, Smooth, Vascular, Oxidative Phosphorylation, Protein-Serine-Threonine Kinases, Tumor Suppressor Proteins|
RATIONALE: DNA damage is present in both genomic and mitochondrial DNA in atherosclerosis. However, whether DNA damage itself promotes atherosclerosis, or is simply a byproduct of the risk factors that promote atherosclerosis, is unknown.
OBJECTIVE: To examine the effect of DNA damage on atherosclerosis, we studied apolipoprotein (Apo)E(-/-) mice that were haploinsufficient for the protein kinase ATM (ataxia telangiectasia mutated), which coordinates DNA repair.
METHODS AND RESULTS: ATM(+/-)/ApoE(-/-) mice developed accelerated atherosclerosis and multiple features of the metabolic syndrome, including hypertension, hypercholesterolemia, obesity, steatohepatitis, and glucose intolerance. Transplantation with ATM(+/+) bone marrow attenuated atherosclerosis but not the metabolic syndrome. ATM(+/-) smooth muscle cells and macrophages showed increased nuclear DNA damage and defective DNA repair signaling, growth arrest, and apoptosis. Metabolomic screening of ATM(+/-)/ApoE(-/-) mouse tissues identified metabolic changes compatible with mitochondrial defects, with increased β-hydroxybutyrate but reduced lactate, reduced glucose, and alterations in multiple lipid species. ATM(+/-)/ApoE(-/-) mouse tissues showed an increased frequency of a mouse mitochondrial "common" deletion equivalent and reduced mitochondrial oxidative phosphorylation.
CONCLUSIONS: We propose that failure of DNA repair generates defects in cell proliferation, apoptosis, and mitochondrial dysfunction. This in turn leads to ketosis, hyperlipidemia, and increased fat storage, promoting atherosclerosis and the metabolic syndrome. Prevention of mitochondrial dysfunction may represent a novel target in cardiovascular disease.
|Alternate Journal||Circ. Res.|
|PubMed Central ID||PMC2982998|
|Grant List||G0802051 / / Medical Research Council / United Kingdom |
MC_U105663142 / / Medical Research Council / United Kingdom
RG/08/009/25841 / / British Heart Foundation / United Kingdom
RG08/009/25841 / / British Heart Foundation / United Kingdom
/ / Biotechnology and Biological Sciences Research Council / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom