Combined Statin and Niacin Therapy Remodels the High-Density Lipoprotein Proteome

Background— Boosting low high-density lipoprotein (HDL) levels is a current strategy for preventing clinical events that result from cardiovascular disease. We previously showed that HDL3 of subjects with coronary artery disease is enriched in apolipoprotein E and that the lipoprotein carries a distinct protein cargo. This observation suggests that altered protein composition might affect the antiatherogenic and antiinflammatory properties of HDL. We hypothesized that an intervention that increases HDL levels—combined statin and niacin therapy—might reverse these changes. Methods and Results— HDL3 isolated from 6 coronary artery disease subjects before and 1 year after combination therapy was analyzed by liquid chromatography–Fourier transform–mass spectrometry. Alterations in protein composition were detected by spectral counting and confirmed with extracted ion chromatograms. We found that combination therapy decreased the abundance of apolipoprotein E in HDL3 while increasing the abundance of other macrophage proteins implicated in reverse cholesterol transport. Treatment-induced decreases in apolipoprotein E levels of HDL3 were validated biochemically in a second group of 18 coronary artery disease subjects. Interestingly, the changes in HDL3 proteome with niacin/statin treatment resulted in a protein composition that more closely resembled that of HDL3 in healthy control subjects. Conclusions— Combined statin and niacin therapy partially reverses the changes in the protein composition seen in HDL3 in coronary artery disease subjects. Our observations raise the possibility that quantifying the HDL proteome could provide insights into the therapeutic efficacy of antiatherosclerotic interventions.