Normal endothelial function in carriers of the apolipoprotein A-1milano mutant despite low HDL-cholesterol levels

Objective: Carriers of apolipoprotein A-IMilano (A-IM), the R173C mutant of apoA-I, are protected against cardiovascular diseases despite very low HDL-cholesterol (HDL-C) levels and hypertriglyceridemia. Aim of the present study was to investigate the endothelial function of A-IM carriers, since low HDL-C levels have been associated with features of endothelial dysfunction. Methods and Results: Plasma concentrations of soluble cell adhesion molecules (sCAMs), and forearm arterial compliance during reactive hyperemia were evaluated in 21 A-IM carriers, 21 healthy subjects with low HDL-C, and 42 controls. Low HDL-C subjects had significantly higher plasma sCAM levels than controls; on the contrary, no differences were detected between A-IM carriers and controls, indicating that HDL from A-IM carriers may be more efficient than control HDL in inhibiting endothelial CAM expression. Thus, HDL were isolated from 6 A-IM carriers and 6 controls, and their ability to inhibit VCAM-1 expression was tested in endothelial cells. HDL from A-IM carriers were twice effective than control HDL in reducing TNFalpha-induced VCAM-I expression, and the inhibition occurred at a transcriptional level, as demonstrated by RT-PCR. Interestingly, no differences in arterial compliance during reactive hyperemia were detected between A-IM carriers and controls. Conclusion: Despite very low HDL-C levels, A-IM carriers do not display features of endothelial dysfunction, such as the increase of circulating sCAM levels and the impairment of arterial compliance, probably because of a superior ability of A-IM containing HDL to protect the endothelium.