title: p53 is required for chloroquine-induced atheroprotection but not insulin sensitization.
abstract: An intact genotoxic stress response appears to be atheroprotective and insulin sensitizing. ATM, mutated in ataxia telangiectasia, is critical for the genotoxic stress response, and its deficiency is associated with accelerated atherosclerosis and insulin resistance in humans and mice. The antimalarial drug chloroquine activates ATM signaling and improves metabolic phenotypes in mice. p53 is a major effector of ATM signaling, but it is unknown if p53 is required for the beneficial effects of chloroquine. We tested the hypothesis that the cardiometabolic effects of chloroquine are p53-dependent. ApoE-null mice with or without p53 were treated with low-dose chloroquine or saline in the setting of a Western diet. After 8 weeks, there was no p53-dependent or chloroquine-specific effect on serum lipids or body weight. Chloroquine reduced plaque burden in mice wild-type for p53, but it did not decrease lesion extent in p53-null mice. However, chloroquine improved glucose tolerance, enhanced insulin sensitivity, and increased hepatic Akt signaling regardless of the p53 genotype. These results indicate that atheroprotection induced by chloroquine is p53-dependent but the insulin-sensitizing effects of this agent are not. Discrete components of the genotoxic stress response might be targeted to treat lipid-driven disorders, such as diabetes and atherosclerosis.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Razani
authors.forename: Chu
authors.initials: C
authors.lastname: Feng
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D001786:Blood Glucose / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002738:Chloroquine / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D002986:Clinical Trials as Topic; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004032:Diet; D005227:Fatty Acids / Q000097:blood; D005260:Female; D006801:Humans; D007328:Insulin; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014280:Triglycerides / Q000097:blood; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D001786:Blood Glucose; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D007328:Insulin; D014280:Triglycerides; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D002738:Chloroquine; D002784:Cholesterol; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases