DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome.
BACKGROUND
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.


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.
Mercer
John R
JR
Division of Cardiovascular Medicine, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, United Kingdom.
Cheng
Kian-Kai
KK
Figg
Nichola
N
Gorenne
Isabelle
I
Mahmoudi
Melli
M
Griffin
Julian
J
Vidal-Puig
Antonio
A
Logan
Angela
A
Murphy
Michael P
MP
Bennett
Martin
M
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D006239:Haplotypes; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D024821:Metabolic Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D055432:Metabolomics; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D010085:Oxidative Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D018797:Cell Cycle Proteins; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases