Altered composition of HDL 3 in FH subjects causing a HDL subfraction with less atheroprotective function

Abstract

Background Subjects with familial hypercholesterolemia (FH) are associated with increased risk of premature atherosclerosis and coronary artery disease (CAD). However, onset of clinically manifested CAD varies widely among subjects with heterozygous FH. The purpose of this study was to investigate whether FH subjects with an identical mutation in the low-density lipoprotein (LDL) receptor gene have a high-density lipoprotein (HDL) 3 that is characterized by a less atheroprotective functions than that of healthy controls and within subgroups of FH. Design Twenty-two adults < 75 years of age with FH and 17 healthy sex- and age-matched controls were included. HDL 3 was isolated and the composition was characterized from each subject, and its ability to suppress tumor necrosis factor(TNF)-α stimulated expression of ICAM-1 on HUVEC was investigated. In addition, plasma level of soluble sICAM-1 and VCAM-1 was measured. Results Compared to controls, FH subjects had lower content of phospholipids in their HDL 3 subfraction and a higher serum ICAM-1 level. No differences in sVCAM-1 were observed. HDL 3 isolated from FH with body mass index(BMI) > 25 and from FH subjects with premature CAD contained higher content of triglycerides compared to the HDL 3 from FH subjects with BMI < 25 and without CAD, respectively. Most important, when testing the function of HDL 3 in the two FH subgroups characterized by elevated BMI and premature CAD, lower inhibition of ICAM-1 expression on HUVEC was observed. Conclusions The altered composition of HDL 3 from FH subjects with BMI > 25 and FH subjects with premature CAD may be responsible for a HDL 3 subfraction with less protective properties assessed as inhibition of ICAM-1 expression on HUVEC consequently leading to more proatherogenic endothelial surface.