The Susceptibility to Diet-Induced Atherosclerosis Is Exacerbated with Aging in C57B1/6 Mice.

The anti-atherogenic activity of HDL is mainly due to their capacity to mediate reverse cholesterol transport (RCT). However, it is not clear to what extent this activity is affected by aging or pro-atherogenic conditions. Three and 24-month-old C57Bl/6 mice were fed an atherogenic diet (high fat, high cholesterol) for 12 weeks. The aged mice displayed a significant reduction in the capacity of HDL to mediate RCT (29.03%, < 0.0006). Interestingly, the atherogenic diet significantly stimulated the RCT process in both young and aged mice (241% and 201%, respectively, < 0.01). However, despite this, significant amounts of cholesterol accumulated in the aortas of mice fed an atherogenic diet as compared to regular chow. The accumulation of cholesterol was more marked in the aortas of aged mice (110% increase, < 0.002). ABCA1 and ABCG1 protein expression on macrophages decreased significantly (52 to 37% reduction, < 0.002), whereas their expression on hepatic cells increased significantly (up to 590% for ABCA1 and 116% for ABCG1, < 0.002). On the other hand, SR-BI protein expression on hepatic cells decreased significantly (42.85%, < 0.0001). ABCG5, ABCG8, and CYP7a protein expression on hepatic cells was also higher in mice fed an atherogenic diet. The increase was age-dependent for both ABCG5 and ABCG8. Our results suggest that the susceptibility to diet-induced atherosclerosis is exacerbated with aging and is a consequence of the dysregulation of the expression levels of membrane cholesterol transporters.