P53 is required for chloroquine-induced atheroprotection but not insulin sensitization

Babak Razani,Chu Feng,Clay F. Semenkovich

doi:10.1194/jlr.m003681

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.

Highlights

An intact genotoxic stress response appears to be atheroprotective and insulin sensitizing
Because macrophages are involved in atherosclerosis as well as insulin resistance [6], the stress kinase Jun N-terminal kinase (JNK) has been shown to promote atherosclerosis [18, 19], and the increased JNK signaling in ataxia telangiectasia mutated (ATM)-deficient macrophages is suppressed by chloroquine in an ATM-dependent manner [9], the absence of p53 might be expected to be associated with hyperactive JNK signaling in macrophages like that seen with ATM deficiency
We assessed this possibility by comparing Thr183/Tyr185 JNK phosphorylation, known JNK-activation sites [20], in thioglycollate-elicited peritoneal macrophages from our wild-type and p53-deficient mice. p53 deficiency was associated with increased JNK phosphorylation following treatment with either of two classic proinflammatory stimuli, LPS and TNF␣ (Fig. 1)