Nitrated apolipoprotein AI/apolipoprotein AI ratio is increased in diabetic patients with coronary artery disease

Abstract

Aims/Hypothesis Recent studies have suggested that determination of HDL function may be more informative than its concentration in predicting its protective role in coronary artery disease (CAD). Apolipoprotein AI (apoAI), the major protein of HDL, is nitrosylated in vivo to nitrated apoAI (NT-apoAI) that might cause dysfunction. We hypothesized that NT-apoAI/apoAI ratio might be associated with diabetes mellitus (DM) in CAD patients. Methods We measured plasma NT-apoAI and apoAI levels in 777 patients with coronary artery disease (CAD) by ELISA. Further, we measured plasma cholesterol efflux potential in subjects with similar apoAI but different NT-apoAI levels. Results We found that median NT-apoAI/apoAI ratio was significantly higher in diabetes mellitus (DM) (n=327) versus non-diabetic patients (n=450). Further analysis indicated that DM, thiobarbituric acid-reactive substances and C-reactive protein levels were independent predictors of higher NT-apoAI/apoAI ratio. There was negative correlation between NT-apoAI/apoAI and use of anti-platelet and lipid lowering drugs. The cholesterol efflux capacity of plasma from 67 individuals with differing NT-apoAI but similar apoAI levels from macrophages in vitro was negatively correlated with NT-apoAI/apoAI ratio. Conclusions Higher NT-apoAI/apoAI ratio is significantly associated with DM in this relatively large German cohort with CAD and may contribute to associated complications by reducing cholesterol efflux capacity.

Association between nitrated lipoproteins and vascular function in type 2 diabetes

“…Here, we found that the concentrations of plasma NT-LDL were much lower than NT-HDL (~ 10 times less). This is in accordance with our previously published reports and others (16,19,29) showing that apoA- (15). Moreover, despite the differences in the degree of nitration on respective apolipoproteins ApoA-I and apoB in these particles, our study revealed a strong positive correlation between NT-HDL and NT-LDL levels.…”

ApoCIII enrichment in HDL impairs HDL-mediated cholesterol efflux capacity

“…But more evidence was needed to elucidate the definite role of HDL-apoCIII in the impairment of cholesterol efflux capacity in diabetic subjects. Other factors have been reported to contribute to the reduced cholesterol efflux, including the increased apoAI nitrosylation 32 and elevated SAA concentration 33 in HDL particles from DM patients. Another interesting finding was that statin users had significantly lower cholesterol efflux capacity compared to the non-statin users.…”

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“…In fact, a possible explanation that the majority of advances in the treatment of dyslipidaemia and in the primary or secondary prevention of CVDs have come from the introduction of cholesterol-lowering drugs 1 .…”

“…It is known that hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation 1 . Dyslipoproteinemia with high levels of total cholesterol, triglycerides and LDL and low levels of HDL and family history of early CAD have been demonstrated to be predisposing factors of early CAD 2 .…”