Affiliation:
1. From the Division of Cardiovascular Medicine (J.R.M., N.F., I.G., M.M., M.B.), Department of Biochemistry (K.-K.C., J.G.), and Institute of Metabolic Sciences (A.V.-P.), University of Cambridge, Addenbrooke’s Hospital; and Medical Research Council Mitochondrial Biology Unit (A.L., M.P.M.), Cambridge, United Kingdom.
Abstract
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
197 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献