RESUMEN
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 ß-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.
Asunto(s)
Aterosclerosis/genética , Daño del ADN/fisiología , Síndrome Metabólico/genética , Mitocondrias/genética , Músculo Liso Vascular/fisiología , Animales , Apolipoproteínas E/genética , Proteínas de la Ataxia Telangiectasia Mutada , Aterosclerosis/metabolismo , Aterosclerosis/fisiopatología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , ADN Mitocondrial/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Grasas de la Dieta/farmacología , Haplotipos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Hiperlipidemias/fisiopatología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/fisiopatología , Metabolómica , Ratones , Ratones Mutantes , Mitocondrias/metabolismo , Músculo Liso Vascular/citología , Fosforilación Oxidativa , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Although the hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are widely used in atherosclerosis to reduce serum cholesterol, statins have multiple other effects, including direct effects on cells of the vessel wall. Recently, DNA damage, including telomere shortening, has been identified in vascular smooth muscle cells (VSMCs) in human atherosclerosis. Although statins reduce DNA damage in vitro, the mechanisms by which they might protect DNA integrity in VSMCs are unknown. We show that human atherosclerotic plaque VSMCs exhibit increased levels of double-stranded DNA breaks and basal activation of DNA repair pathways involving ataxia telangiectasia-mutated (ATM) and the histone H2AX in vivo and in vitro. Oxidant stress induced DNA damage and activated DNA repair pathways in VSMCs. Statin treatment did not reduce oxidant stress or DNA damage but markedly accelerated DNA repair. Accelerated DNA repair required both the Nijmegen breakage syndrome (NBS)-1 protein and the human double minute protein Hdm2, accompanied by phosphorylation of Hdm2, dissociation of NBS-1 and Hdm2, inhibition of NBS-1 degradation, and accelerated phosphorylation of ATM. Statin treatment reduced VSMC senescence and telomere attrition in culture, accelerated DNA repair and reduced apoptosis in vivo after irradiation, and reduced ATM/ATR (ATM and Rad3-related) activity in atherosclerosis. We conclude that statins activate a novel mechanism of accelerating DNA repair, dependent on NBS-1 stabilization and Hdm2. Statin treatment may delay cell senescence and promote DNA repair in atherosclerosis.
Asunto(s)
Aterosclerosis/tratamiento farmacológico , Proteínas de Ciclo Celular/metabolismo , Reparación del ADN/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteínas Nucleares/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Aterosclerosis/metabolismo , Proteínas de Ciclo Celular/genética , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Senescencia Celular/genética , Colesterol/metabolismo , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Endotelio Vascular/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Ratones , Proteínas Nucleares/genética , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Conejos , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Atherosclerosis is the commonest cause of death in the Western world. The atherosclerotic plaque shows evidence of DNA damage, activation of damage repair pathways, p53 expression and apoptosis, involving a variety of different cell types. This review summarises the evidence for DNA damage in atherosclerosis, the likely stimuli inducing damage, and the increasing role of p53 in mediating apoptosis and its consequences in atherosclerosis.
Asunto(s)
Apoptosis , Daño del ADN , Proteína p53 Supresora de Tumor/biosíntesis , Enfermedades Vasculares , Animales , Apoptosis/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Humanos , Estrés Oxidativo/genética , Proteína p53 Supresora de Tumor/genética , Enfermedades Vasculares/genética , Enfermedades Vasculares/metabolismo , Enfermedades Vasculares/patologíaRESUMEN
There is increasing evidence that human atherosclerosis is associated with damage to the DNA of both circulating cells, and cells of the vessel wall. Reactive oxygen species are the most likely agents inducing DNA damage in atherosclerosis. DNA damage produces a variety of responses, including cell senescence, apoptosis and DNA repair. This review summarises the evidence for DNA damage in atherosclerosis, the cellular responses to damage and the mechanisms of signalling DNA damage.