HDL lowers the risk for atherosclerotic cardiovascular disease by promoting cholesterol efflux from macrophage foam cells. However, other antiatherosclerotic properties of HDL are poorly understood. To test the hypothesis that the lipoprotein carries proteins that might have novel cardioprotective activities, we used shotgun proteomics to investigate the composition of HDL isolated from healthy subjects and subjects with coronary artery disease (CAD). Unexpectedly, our analytical strategy identified multiple complement-regulatory proteins and a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity. Many acutephase response proteins were also detected, supporting the proposal that HDL is of central importance in inflammation. Mass spectrometry and biochemical analyses demonstrated that HDL 3 from subjects with CAD was selectively enriched in apoE, raising the possibility that HDL carries a unique cargo of proteins in humans with clinically significant cardiovascular disease. Collectively, our observations suggest that HDL plays previously unsuspected roles in regulating the complement system and protecting tissue from proteolysis and that the protein cargo of HDL contributes to its antiinflammatory and antiatherogenic properties.

Many anthropometric, clinical, and biochemical factors can infl uence the composition and size of lipoprotein subpopulations. It has been demonstrated that the prevalence of small dense LDL particles increases cardiovascular (CV) risk ( 1-3 ) and that the distribution of differently sized particles in HDL infl uences its anti-atherogenic effects ( 4-8 ).In the HDL-Atherosclerosis Treatment Study (HATS), in which patients with coronary disease and low HDL-cholesterol (HDL-C) were treated with a combinations of simvastatin, niacin, and antioxidants, the therapy had a selective effect on composition of lipoprotein subpopulations and therefore on consequent changes in the coronary artery stenosis ( 9 ). Although the composition of lipoprotein subpopulations contributes substantially to plasma atherogenicity, it is impractical to measure its variations as the assays have not been standardized and are expensive and thus not suitable for routine use.We have established that two markers of CV risk, namely cholesterol esterifi cation rate in apolipoprotein Abstract We examined the association between rate of cholesterol esterifi cation in plasma depleted of apolipoprotein B-containing lipoproteins (FER HDL ), atherogenic index of plasma (AIP) [(log (TG/HDL-C)], concentrations, and size of lipoproteins and changes in coronary artery stenosis in participants in the HDL-Atherosclerosis Treatment Study. A total of 160 patients was treated with simvastatin (S), niacin (N), antioxidants (A) and placebo (P) in four regimens. FER HDL was measured using a radioassay; the size and concentration of lipoprotein subclasses were determined by nuclear magnetic resonance spectroscopy. The S+N and S+N+A therapy decreased AIP and FER HDL , reduced total VLDL (mostly the large and medium size particles), decreased total LDL particles (mostly the small size), and increased total HDL particles (mostly the large size). FER HDL and AIP correlated negatively with particle sizes of HDL and LDL, positively with VLDL particle size, and closely with each other ( r = 0.729). Changes in the proportions of small and large lipoprotein particles, which were refl ected by FER HDL and AIP, corresponded with fi ndings on coronary angiography. Logistic regression analysis of the changes in the coronary stenosis showed that probability of progression was best explained by FER HDL ( P = 0.005). FER HDL and AIP refl ect the actual composition of the lipoprotein spectrum and thus predict both the cardiovascular risk and effectiveness of therapy. AIP is already available for use in clinical practice as it can be readily calculated from the routine lipid profi le. -Dobiášová, M., J. Frohlich, M. Šedová, M. C. Cheung, and B. G. Brown. Cholesterol esterifi cationThe study was supported by HDL-C, HDL-cholesterol; log(TG/HDL-C), logarithmically transformed ratio of molar concentrations of triglyceride and HDL-cholesterol; N, niacin; P, placebo; S, simvastatin; TC, total cholesterol; TG, triglyceride .

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Abstract-One strategy for treating coronary artery disease (CAD) patients with low HDL cholesterol (HDL-C) is to maximally increase the HDL-C to LDL-C ratio by combining lifestyle changes with niacin (N) plus a statin. Because HDL can prevent LDL oxidation, the low-HDL state also may benefit clinically from supplemental antioxidants. Lipoprotein changes over 12 months were studied in 153 CAD subjects with low HDL-C randomized to take simvastatin and niacin (S-N), antioxidants (vitamins E and C, ␤-carotene, and selenium), S-N plus antioxidants (S-NϩA), or placebo. Mean baseline plasma cholesterol, triglyceride, LDL-C, and HDL-C levels of the 153 subjects were 196, 207, 127, and 32 mg/dL, respectively. Without S-N, lipid changes were minor. The S-N and S-NϩA groups had comparably significant reductions (PՅ0.001) in plasma cholesterol, triglyceride, and LDL-C. However, increases in HDL-C, especially HDL 2 -C, were consistently higher in the S-N group than in the S-NϩA group (25% vs 18% and 42% vs 0%, respectively). With S-N, but not with S-NϩA, there was a selective increase in apolipoprotein (apo) A-I (64%) in HDL particles containing apo A-I but not A-II [Lp(A-I)] and their particle size. Thus, in CAD patients with low HDL-C, S-N substantially increased HDL 2 -C, Lp(A-I), and HDL particle size. These favorable responses were blunted by the antioxidants used owing to a striking selective effect on Lp(A-I

A B S T R A C T To study apolipoprotein A-II, a simple, precise, and accurate immunodiffusion assay was developed and applied in a population sample of industrial employees. Apolipoprotein A-II (A-II) did not increase with age in men (r = -0.20, n = 172), but showed a slight increase with age in women (0.1 mg/dl per yr, r = 0.20, n = 188). A-II correlated significantly with apolipoprotein A-I (A-I) (r = 0.71) and high density lipoprotein (HDL) cholesterol (men, r = 0.64; women, r = 0.49). The A-I/A-II ratio was significantly related to HDL cholesterol (men, r = 0.29; women, r = 0.44). Women on no medication (n = 92) had A-II levels similar to men (34+5 and 33+5 mg/dl, mean±+SD, respectively), whereas women on oral contraceptives or estrogens had significantly higher levels (39±6 mg/dl, n = 75, P < 0.01). The plasma A-I/A-Il weight ratio was 3.6±0.4 for men and 3.8±0.5 for women. In the d = 1.10-1.21 subfraction, both males and females had similar A-I, A-II, and HDL cholesterol levels (men: mean, 97, 27, and 32 mg/dl, respectively; women: mean, 104, 28, and 36 mg/dl, respectively). Women had approximately twice the amount of A-I, A-II, and HDL cholesterol than men in the d = 1.063-1.10 fraction (men: mean, 10, 2, aind 10 mg/dl, respectively; women: mean, 24, 4, and 19 mg/dl, respectively). The A-I/A-II weight ratio in the d = 1.063-1.10 fraction (men, 5.1±0.7; women, 6.1±1.3) was significantly greater (P < 0.01) than that in the d = 1.10-1.21 fraction (men, 3.7 ±0.2; women, 3.8±0.2). Furthermore, the weight ratio of cholesterol to total apoprotein A in the d = 1.063-1.10 fraction (men, 0.75±0.09; women, 0.67±0.05) was significantly higher (P < 0.01) than that found in the d = 1.10-1.21 fraction (men, 0.26±0.04, women, 0.28 A preliminary report of part of this work was presented at the 49th Annual Scientific Meeting of the American Heart Association in Miami, Fla. and was published in abstract form in 1976. Circulation. 54 (Suppl 2): 367.Received for publication 21 ±0.05). Thus, the compositions of HDL hydrated density subclasses are significantly different from each other. These results suggest that the differences in HDL between men and women are due primarily to differences in the relative proportions of HDL subclasses rather than to the intrinsic differences in HDL structure.