High-Density Lipoprotein Cholesterol Efflux, Nitration of Apolipoprotein A-I, and Endothelial Function in Obese Women

Abstract

Subjects at risk for atherosclerosis may have dysfunctional high-density lipoprotein (HDL) despite normal cholesterol content in plasma. We considered whether efflux of excess cellular cholesterol to HDL from obese subjects is associated with impaired arterial endothelial function, a biomarker of cardiovascular risk. Fifty-four overweight (body mass index [BMI] 25 – 29.9 kg/m2) or obese women (BMI ≥ 30 kg/m2), age 46 ± 11 years, were enrolled in a worksite wellness program. HDL cholesterol averaged 57 ± 17 mg/dL and was inversely associated with BMI (r= −0.419, P= 0.002). Endothelial function was assessed by brachial artery flow-mediated dilation (FMD). Cholesterol efflux from 3H-cholesterol-labeled BHK cells transfected with the ATP-binding cassette transporter 1 (ABCA1) showed 8.2 to 22.5% cholesterol efflux over 18 hours when incubated with 1% serum and was positively correlated with FMD (P <0.05), especially in the 34 subjects with BMI ≥ 30 kg/m2 (r= 0.482, P= 0.004). This relation was independent of age, HDL or low-density lipoprotein cholesterol (LDL) concentrations in plasma, blood pressure or insulin resistance by stepwise multiple regression analysis (β= 0.31, R2= 0.21, P= 0.007). Nitration of apoA-I tyrosine residues (by sandwich ELISA) was significantly higher in women with BMI ≥ 30 kg/m2 and the lowest cholesterol efflux than in women with BMI 25 – 29.9 kg/m2 and the highest cholesterol efflux (P= 0.01). We conclude that decreased cholesterol efflux via the ABCA1 transporter is associated with increased nitration of apoA-I in HDL and is an independent predictor of impaired endothelial function in women with BMI ≥ 30 kg/m2. This finding suggests that functional measures of HDL may be better markers for cardiovascular risk than HDL cholesterol levels in this population.

Cholesterol Efflux and Reverse Cholesterol Transport

“…In addition, in a population of healthy subjects, ABCA1-mediated serum CEC was inversely correlated with pulse wave velocity, an index of arterial stiffness, independent of HDL-C serum levels (Favari et al 2013). A work measuring the flow-mediated dilation, as a parameter of endothelial function, showed a positive correlation with the ABCA1-mediated efflux pathway confirming the concept that the functional measures of HDL might be a better marker for cardiovascular risk rather than HDL cholesterol levels (Vazquez et al 2012). Recently, Li and colleagues provided data indicating that individuals in the top tertile of CEC had a moderately increased risk of a composite cardiovascular end point of incident myocardial infarction, stroke, or death during 3 years of follow-up (Li et al 2013).…”

Cerebral Small Vessel Disease Burden Is Increased in Systemic Lupus Erythematosus

“…41 The reason why cholesterol might relate to PVS in SLE is unknown and could be spurious given our study’s lack of power, but HDL can become dysfunctional resulting in inflammation 42,43 and endothelial dysfunction. 44 …”

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

“…Although there appears to be a tendency towards higher plasma NT-apoAI levels in diabetes and CAD subjects, the studies were small and used gas chromatography-mass spectrometry methods that are not suitable for larger cohort studies. Previously, we developed a novel 20 enzyme-linked immunosorbent assay (ELISA), which was confirmed by both Western blot analysis 20 and mass spectrometry 19 . This sensitive and specific ELISA method is suitable to quantify human NT-apoAI levels in a large population.…”

“…In addition, higher levels of NT-apoAI were found in patients with cardiovascular disease in both the circulation and in atheroma 13, 14, 16 . Recently, Vazquez et al reported a significantly higher level of circulating NT-apoAI in obese women 19 . Although there appears to be a tendency towards higher plasma NT-apoAI levels in diabetes and CAD subjects, the studies were small and used gas chromatography-mass spectrometry methods that are not suitable for larger cohort studies.…”