P619Differential high density lipoprotein proteomic profile in heterozygous familial hypercholesterolemia

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Abstract

Increasing attention has been focussed on the concept of high density lipoprotein (HDL) quality rather than quantity as a key determinant of HDL-mediated atheroprotection. Heterozygous familial hypercholesterolemia (hFH) patients show a high prevalence of premature coronary artery disease (CAD). By applying a proteomic expression profiling we have investigated the HDL proteome of hFH patients with and without previous CAD in order to investigate changes in the HDL of patients with active atherosclerosis.

Methods

HDL were obtained by plasma ultracentrifugation in density gradients and characterized by bidimensional-electrophoresis (2-DE) and mass-spectrometry (MALDI-TOF-TOF) in 10 families of the hFH Spanish -SAFEHEART cohort (3 individuals/family: 2 patients with genetic diagnostic of hFH+/- clinical evidence of CAD and a control without hFH).

Results

The HDL proteomic profile of hFH patients and healthy controls revealed four major functional groups of proteins: acute phase response proteins (alpha-1-antitrypsin, transthyretin), lipid metabolism enzymes (lecithin-cholesterol acyltransferase (LCAT)), anti-oxidant proteins (paraoxonase-1) and apolipoproteins (Apo-AI, -AIV, -D, -E, -J, -L1, and –M). In hFH-patients, the presence of CAD was associated with significant changes in LCAT and Apo-L1 proteomic profile. LCAT (P04180) was identified as a series of 6 spots (68-65 kDa; pI range 4.3-4.7) with a 1.6-fold increase of the most acid spot and a 1.5-fold decrease of the 3 more basic spots (p < 0.05). Apo-L1 (O14791) was identified as two clusters of 6 protein spots each, with molecular masses of 44 and 38 kDa and a pI range of 5.5-6.5. The presence of both clusters was confirmed by western blot analysis. In both clusters the protein spots with a pI of 6.1 showed more than 3-fold decrease in patients with hFH and previous CAD when compared to hFH patients without CAD. In addition, patients with genetic diagnostic of hFH showed a 2.5-fold decrease in the Apo-L1 spot with a pI of 5.7 of the 44 kDa cluster when compared to their healthy relatives.

Conclusions

hFH-patients with previous manifestation of CAD show significant changes in the distribution of Apo-L1 (an apoptosis-related protein) and in LCAT (a metabolic enzyme involved in cholesterol transfer and generation of Apo-L1 containing fractions) in the HDL particles.

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