Myeloperoxidase mediated HDL oxidation and HDL proteome changes do not contribute to dysfunctional HDL in Chinese subjects with coronary artery disease

<div><p>High density lipoprotein (HDL) cholesterol levels and cholesterol efflux capacity (CEC) are inversely correlated with coronary artery disease (CAD) risk. Myeloperoxidase (MPO) derived oxidants and HDL proteome changes are implicated in HDL dysfunction in subjects with CAD in the United States; however, the effect of MPO on HDL function and HDL proteome in ethnic Chinese population is unknown. We recruited four matched ethnic Chinese groups (20 patients each): subjects with 1) low HDL levels (HDL levels in men <40mg/dL and women <50mg/dL) and non-CAD (identified by coronary angiography or cardiac CT angiography); 2) low HDL and CAD; 3) high HDL (men >50mg/dL; women >60mg/dL) with no CAD; and 4) high HDL with CAD. Serum cytokines, serum MPO levels, serum CEC, MPO-oxidized HDL tyrosine moieties, and HDL proteome were assessed by mass spectrometry individually in the four groups.</p><p>The cytokines, MPO levels, and HDL proteome profiles were not significantly different between the four groups. As expected, CEC was depressed in the entire CAD group but more specifically in the CAD low-HDL group. HDL of CAD subjects had significantly higher 3-nitrotyrosine than non-CAD subjects, but the MPO-specific 3-chlorotyrosine was unchanged; CEC in the CAD low-HDL group did not correlate with either HDL 3-chlorotyrosine or 3-nitrotyrosine levels. Neither 3-chlorotyrosine, which is MPO-specific, nor 3-nitrotyrosine generated from MPO or other reactive nitrogen species was associated with CEC. MPO mediated oxidative stress and HDL proteome composition changes are not the primary cause HDL dysfunction in Chinese subjects with CAD. These studies highlight ethnic differences in HDL dysfunction between United States and Chinese cohorts raising possibility of unique pathways of HDL dysfunction in this cohort.</p></div

Cholesterol efflux capacity is decreased in coronary artery disease patients in China.

<p>(A) Cholesterol efflux capacity (CEC) in coronary artery disease (CAD) subjects compared to healthy controls (Non CAD) cohort in the entire cohort. (B) CEC shows differences in the CAD and non CAD cohort in the Low HDL group only and (C) shows differences in the high HDL cohort only. CEC is decreased in CAD group overall and specifically in the low HDL cohort, even as the high HDL cohort showed no differences between the CAD and non CAD group (*p value<0.05).</p

Plasma myeloperoxidase (MPO) levels and activity are unchanged in coronary artery disease patients in China.

<p>Plasma MPO levels in subjects with coronary artery disease (CAD) and without CAD (Non CAD) are represented by box plots of (A) All subjects (n = 40/group), (B) Low HDL subjects alone (n = 20/group) and (C) High HDL subjects alone (n = 20/group). MPO activity is represented by high density lipoprotein (HDL) 3-chlorotyrosine and 3-nitrotyrosine levels normalized to tyrosine levels determined by tandem mass spectrometry. Box plots display the distributions of HDL levels (log scale; log) of 3-chlorotyrosine in (D) All subjects (n = 40/group), (E) Low HDL subjects only (n = 20/group) and (F) High HDL subjects only (n = 20/group) between CAD and Non CAD groups. HDL 3-nitrotyrosine levels represented by box plot (log scale, log) of (G) All subjects (n = 40/group), (H) Low HDL subjects only (n = 20/group), and (I) High HDL subjects only (n = 20/group) between CAD and Non CAD groups. The plasma levels of MPO were not different between CAD and Non CAD subjects in the different cohorts. The HDL 3 chlorotyrosine levels were not different between groups except in the Low HDL subjects were the HDL 3-chlorotyrosine levels were elevated in the CAD subjects than in the non CAD subjects. The HDL 3-nitrotyrosine levels were elevated in the CAD subjects in the entire cohort and in both the low and high HDL subjects. The length of the box defines the interquartile range (IQR). Medians are reported for each group on the raw scale above the respective bar graphs. *denotes p<0.05.</p

Demographic characteristics of the controls and coronary artery disease patients.

<p>Demographic characteristics of the controls and coronary artery disease patients.</p

High-density lipoprotein protein composition is not altered in Chinese coronary artery disease subjects irrespective of high-density lipoprotein levels.

<p>The relative enrichment of 25 proteins in the high density lipoprotein (HDL) fraction of with and without coronary artery disease (CAD, Non CAD; n = 10 each) is represented by peptide index as described in the Methods section. No significant changes were observed between CAD and Non CAD subjects in both the cohorts. ALB-Albumin; A1AT-Alpha 1 antitrypsin; APO E-Apolipoprotein E; APOA1-Apolipoprotein A-I; APOA2-Apolipoprotein A-II; APOA4-Apolipoprotein A-IV; APOB-Apolipoprotein B; APOC1-Apolipoprotein C1; APOC2-Apolipoprotein C-II; APOC3-Apolipoprotein C3; APOC4- Apolipoprotein C-IV; APOD- Apolipoprotein D; APOF-Apolipoprotein F; C4A-Complement fragment 4A; C9-Complement 3; CETP-Cholesterol Ester transfer protein; CLU-Clusterin; FGA-Fibrinogen alpha; PCYOX1-Prenylcysteine oxidase 1; PLA2G7-Platelet-Activating Factor Acetylhydrolase; PLTP-Phospholipid transfer protein; PON1-Serum paraoxonase/arylesterase 1; SAA-Serum Amyloid A protein; SHBG- Sex hormone-binding globulin; VTN-Vitronectin.</p