Background and Purpose Protein modification by sugars and lipids lead to formation of potentially toxic advanced glycation and lipoxidation end-products (AGE/ALE). Oxidative and carbonyl stress by these compounds and their precursors, such as reactive carbonyl intermediaries, are thought to play an important role in vascular complications of various diseases, especially diabetes. Pyridoxamine (PM), which inhibits AGE/ALE formation by trapping carbonyl moieties, has been shown to decrease microvascular complications in diabetic and obese non-diabetic rat models. However, PM also profoundly lowered cholesterol and triglycerides in these rats. If the same occurs in atherosclerosis-prone mice, it will limit its ability to test the effect of carbonyl scavenging in macrovascular disease. Therefore, we tested whether PM would have a hypolipidemic effect on an atherosclerosis-prone mouse-model, in which lipid metabolism is markedly different than rats.
Methods Male and female low density lipoprotein receptor deficient mice (LDLR -/-) were fed a western type diet consisting of 21% (w/w) butterfat and 0.15% (w/w) cholesterol for 12 weeks - with or without PM (2g/L) added to their drinking water. At baseline, 6 weeks and 12 weeks, measurements of plasma cholesterol, triglyceride (TG) and serum amyloid A (SAA) were obtained.
Results At the end of 12 weeks, cholesterol, TG and SAA levels were markedly increased in all groups. There was no statistically significant difference, between treatment (Rx) and control groups, in average serum cholesterol for males (1745 vs. 1784 mg/dl) and TG for females (254 vs. 242 mg/dl). Compared to controls, there was a slightly higher average serum TG level in the male Rx group (729 vs. 492 mg/dl, p =0.01), while there was a slightly lower average cholesterol in the female Rx group (1097 vs. 1354 mg/dl, p = 0.02). SAA at 12 weeks was significantly lower in the female Rx groups compared to controls (13.8 vs. 51.2, p ≤ 0.01). There were no significant differences in SAA in the males, although there was a trend downwards in the Rx group (64.3 vs. 74.6 mcg/ml, p = 0.22).
Conclusion In LDLR -/- mice fed a western type diet, PM did not have the hypolipidemic effect that was seen in diabetic and obese non-diabetic rat models. These mice will therefore be a good model to test the effect of carbonyl scavengers on the development of atherosclerosis.