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

Carriers of the apolipoprotein A-IMilano (apoA-IM) mutant show severe reductions in the plasma concentration of antiatherogenic HDL but do not present with preclinical atherosclerosis and premature CHD. Aim of the present study was to investigate endothelial function in A-IM carriers, since low HDL-C levels have been associated with features of endothelial dysfunction. Plasma concentrations of soluble cell adhesion molecules (sCAMs) and forearm arterial compliance (FAC) 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 (sVCAM-1: 656.3±49.3 vs 502.6±25.5 ng/ml; sICAM-1: 335.6±21.5 vs 267.0±8.9 ng/ml; sE-selectin: 62.9±4.1 vs 47.9±3.0 ng/ml); on the contrary, no differences were detected between A-IM carriers (sVCAM-1: 550.6±32.1 ng/ml; sICAM-1: 309.8±26.9 ng/ml; sE-selectin: 52.3±4.3 ng/ml) and controls. Low HDL-C subjects had lower FAC than controls, while no differences were detected between A-IM carriers and controls. These results suggest that HDL from A-IM carriers may be more efficient than control HDL in modulating endothelial function. To test this hypothesis, plasma HDL were isolated from 6 A-IM carriers and 6 controls, and their ability to inhibit VCAM-1 expression and to induce eNOS was tested in cultured endothelial cells. A-IM HDL were two times more effective than control HDL in reducing TNFalpha-induced VCAM-1 expression; the inhibition occurred at a transcriptional level, as demonstrated by RT-PCR. In addition, cells exposed to A-IM HDL showed higher expression of eNOS than cells treated with control HDL. In conclusion, despite the 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 HDL to protect the endothelium.