p53 is required for chloroquine-induced atheroprotection but not insulin sensitization

Area of Science:

• Cardiovascular Science
• Metabolic Science
• Genetics

Background:

• The genotoxic stress response, regulated by ATM (ataxia telangiectasia mutated), is linked to protection against atherosclerosis and improved insulin sensitivity.
• ATM deficiency accelerates atherosclerosis and insulin resistance.
• Chloroquine, an antimalarial, activates ATM signaling and improves metabolic health in mice.

Purpose of the Study:

• To investigate whether the cardiometabolic effects of chloroquine are dependent on p53, a key ATM signaling effector.
• To determine if p53 is required for chloroquine's atheroprotective and insulin-sensitizing properties.

Main Methods:

• ApoE-null mice, with and without functional p53, were fed a Western diet and treated with chloroquine or saline for 8 weeks.
• Evaluated serum lipids, body weight, atherosclerotic plaque burden, glucose tolerance, and insulin sensitivity.
• Assessed hepatic Akt signaling pathways.

Main Results:

• Chloroquine significantly reduced atherosclerotic plaque burden in p53-wild-type mice but not in p53-null mice, indicating a p53-dependent atheroprotective effect.
• Chloroquine improved glucose tolerance and insulin sensitivity in both p53-wild-type and p53-null mice.
• Hepatic Akt signaling was enhanced by chloroquine irrespective of p53 status.
• No significant p53-dependent or chloroquine-specific effects on serum lipids or body weight were observed.

Conclusions:

• Chloroquine's atheroprotective effects are mediated through a p53-dependent pathway.
• Chloroquine's insulin-sensitizing effects are independent of p53.
• Targeting specific components of the genotoxic stress response could offer therapeutic strategies for atherosclerosis and diabetes.