HDL functions and their interaction in patients with ST Elevation Myocardial Infarction: a case control study

Abstract Background : Recent studies emphasize the importance of HDL function over HDL cholesterol measurement, as an important risk for cardiovascular diseases (CVD). We compared the HDL function of patients with Acute Coronary Syndrome (ACS) and healthy controls. Methods : We measured cholesterol efflux capacity of HDL using THP-1 macrophages labelled with fluorescently tagged (BODIPY) cholesterol. Paraoxonase and arylesterase activity of PON1 enzyme were assessed by spectrophotometric methods. Results : We recruited 151 ACS patients and 110 controls. The HDL function of all patients during acute phase and at six month follow-up was measured. The mean age of the patients and controls was 51.7 and 43.6 years respectively. The mean HDL cholesterol/apolipoprotein A-I levels (ratio) of patients during acute phase, follow-up and of controls were 40.2 mg/dl/ 112.5 mg/dl (ratio= 0.36), 38.3 mg/dl/ 127.2 mg/dl (ratio= 0.30) and 45.4 mg/dl/ 142.1 mg/dl (ratio=0.32) respectively. The cholesterol efflux capacity (CEC) of HDL was positively correlated with apolipoprotein A-I levels during acute phase (r = 0.19, p = 0.019), follow-up (r = 0.26, p = 0.007) and of controls (r = 0.3, p = 0.0012) but not with HDL-C levels (acute phase: r = 0.07, p = 0.47; follow-up: r = 0.1 , p = 0.2; control: r = 0.02, p = 0.82). Higher levels of cholesterol efflux capacity, PON1 activity and apolipoprotein A-I were associated with lower odds of development of ACS. We also observed that low CEC is associated with higher odds of having ACS if PON1 activity of HDL is also low and vice versa. Conclusion : ACS is associated with reduced HDL functions which improves at follow-up. The predicted probability of ACS depends upon individual HDL functions and the interactions between them.

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HDL functions and their interaction in patients of ST Elevation MI Acute Coronary Syndrome: a case control study

10.21203/rs.2.20893/v2 ◽

2020 ◽

Author(s):

Himani Thakkar ◽

Vinnyfred Vincent ◽

Ambuj Roy ◽

Sandeep Singh ◽

Lakshmy Ramakrishnan ◽

...

Keyword(s):

Acute Phase ◽

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Pon1 Activity ◽

Cholesterol Efflux Capacity ◽

Coronary Syndrome ◽

Hdl Function ◽

Apolipoprotein A ◽

The Mean

Abstract Background: Recent studies emphasize the importance of HDL function over HDL cholesterol measurement, as an important risk for cardiovascular diseases (CVD). We compared the HDL function of patients with Acute Coronary Syndrome (ACS) and healthy controls.Methods: We measured cholesterol efflux capacity of HDL using THP-1 macrophages labelled with fluorescently tagged (BODIPY) cholesterol. Paraoxonase and arylesterase activity of PON1 enzyme were assessed by spectrophotometric methods. Results: We recruited 151 ACS patients and 110 controls. The HDL function of all patients during acute phase and at six month follow-up was measured. The mean age of the patients and controls was 51.7 and 43.6 years respectively. The mean HDL cholesterol/apolipoprotein A-I levels (ratio) of patients during acute phase, follow-up and of controls were 40.2 mg/dl/ 112.5 mg/dl (ratio= 0.36), 38.3 mg/dl/ 127.2 mg/dl (ratio= 0.30) and 45.4 mg/dl/ 142.1 mg/dl (ratio=0.32) respectively. The cholesterol efflux capacity (CEC) of HDL was positively correlated with apolipoprotein A-I levels during acute phase (r = 0.19, p = 0.019), follow-up (r = 0.26, p = 0.007) and of controls (r = 0.3, p = 0.0012) but not with HDL-C levels (acute phase: r = 0.07, p = 0.47; follow-up: r = 0.1 , p = 0.2; control: r = 0.02, p = 0.82). Higher levels of cholesterol efflux capacity, PON1 activity and apolipoprotein A-I were associated with lower odds of development of ACS. We also observed that low CEC is associated with higher odds of having ACS if PON1 activity of HDL is also low and vice versa. Conclusion: ACS is associated with reduced HDL functions which improves at follow-up. The predicted probability of ACS depends upon individual HDL functions and the interactions between them.

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HDL functions and their interaction in patients of Acute Coronary Syndrome: a case control study

10.21203/rs.2.20893/v1 ◽

2020 ◽

Author(s):

Himani Thakkar ◽

Vinnyfred Vincent ◽

Ambuj Roy ◽

Sandeep Singh ◽

Lakshmy Ramakrishnan ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Acute Phase ◽

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Coronary Syndrome ◽

Hdl Function ◽

Apolipoprotein A ◽

Predicted Probability ◽

The Mean

Abstract Aim: Recent studies emphasize the importance of HDL function over HDL cholesterol measurement, as an important risk for cardiovascular diseases (CVD). We compared the HDL function of patients with Acute Coronary Syndrome (ACS) and healthy controls. Methods: We measured cholesterol efflux capacity of HDL using THP-1 macrophages labelled with fluorescently tagged (BODIPY) cholesterol. Paraoxonase and arylesterase activity of PON1 enzyme were assessed by spectrophotometric methods. Results: We recruited 151 ACS patients and 110 controls. The HDL function of all patients during acute phase and at six month follow-up was measured. The mean age of the patients and controls was 51.7 and 43.6 years respectively. The mean HDL cholesterol/apolipoprotein A-I levels of patients during acute phase, follow-up and of controls were 40.2 mg/dl/ 112.5 mg/dl, 38.3 mg/dl/ 127.2 and 45.4 mg/dl/ 142.1 mg/dl respectively. The cholesterol efflux capacity of HDL was positively correlated with apolipoprotein A-I levels during acute phase (r = 0.19, p = 0.019), follow-up (r = 0.26, p = 0.007) and of controls (r = 0.3, p = 0.0012) but not with HDL-C levels. Higher levels of CEC, PON 1 activity and apolipoprotein A-I were associated with lower odds of development of ACS. We also observed that combined analysis of two HDL functions could improve the predicted probability of ACS development. Conclusion: ACS is associated with reduced HDL functions which improves at follow-up. The predicted probability of ACS depends upon individual HDL functions and the interactions between them.

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Serum cholesterol efflux capacity is associated with coronary plaque progression in patients with coronary heart disease

European Heart Journal ◽

10.1093/eurheartj/ehab724.1389 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

X Q Wang ◽

S Feng ◽

X Y Shu ◽

C D Yang ◽

R Y Zhang

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Coronary Angiography ◽

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Coronary Plaque ◽

Plaque Progression ◽

Cholesterol Efflux Capacity ◽

Hdl Function

Abstract Background Coronary plaque progression is a major risk factor of adverse cardiac events in patients with coronary heart disease (CHD). Emerging evidence showed that attenuated high-density lipoprotein (HDL) function measured by cholesterol efflux capacity (CEC) was associated with development of atherosclerosis independent of HDL cholesterol level. In this study, we sought to investigate whether CEC is a predictor for coronary plaque progression in CHD patients. Methods We consecutively enrolled CHD patients from January 2017 to August 2019 in our Hospital who underwent elective percutaneous coronary intervention and had at least one non-target coronary lesion. Follow-up coronary angiography were performed at around 12 months. Fluorescence-labeled cholesterol and J774 macrophages were used to measure the CEC of ApoB-depleted serum sample from all patients. Quantitative coronary angiography (QCA) was performed both at baseline and follow-up to analyze the plaque progression. Results A total of 430 CHD patients with 586 non-target coronary lesions were included in the final analysis. During a mean follow-up time of 381.04±59.52 days, patients with decreased CEC presented more severe plaque progression (net luminal loss in highest to lowest CEC quartile: 0.22±0.42mm vs 0.20±0.41mm vs 0.13±0.36mm vs 0.11±0.34mm, p=0.035). In multivariate analysis, baseline CEC was independently associated with coronary plaque progression after adjustment for traditional risk factors including HDL cholesterol and ApoA-I, no matter treated as categorical variable (OR: 0.382 [95% CI 0.180–0.781] for highest to lowest quartile) or continuous variable (OR: 0.522 [95% CI 0.373–0.714] for per SD increase]. Furthermore, CEC demonstrated a better power in predicting coronary plaque progression compared with HDL cholesterol concentration (AUC=0.644 vs 0.514). Conclusions This study suggests that HDL function reflected by serum CEC is an independent predictor for coronary plaque progression in CHD patients. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Natural Science Foundation of China, Shanghai Municipal Commission of Health and Family Planning

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Dysfunctional High-Density Lipoproteins Are Associated With a Greater Incidence of Acute Coronary Syndrome in a Population at High Cardiovascular Risk

Circulation ◽

10.1161/circulationaha.119.041658 ◽

2020 ◽

Vol 141 (6) ◽

pp. 444-453 ◽

Cited By ~ 9

Author(s):

María Trinidad Soria-Florido ◽

Olga Castañer ◽

Camille Lassale ◽

Ramon Estruch ◽

Jordi Salas-Salvadó ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Cardiovascular Risk ◽

Cholesterol Efflux ◽

Hdl Cholesterol ◽

Functional Characteristics ◽

Cholesterol Efflux Capacity ◽

Inflammatory Index ◽

Coronary Syndrome ◽

Apolipoprotein A ◽

Sphingosine 1 Phosphate

Background: Studies have failed to establish a clear link between high-density lipoprotein (HDL) cholesterol and cardiovascular disease, leading to the hypothesis that the atheroprotective role of HDL lies in its biological activity rather than in its cholesterol content. However, to date, the association between HDL functional characteristics and acute coronary syndrome has not been investigated comprehensively. Methods: We conducted a case-control study nested within the PREDIMED (Prevención con Dieta Mediterránea) cohort, originally a randomized trial in which participants followed a Mediterranean or low-fat diet. Incident acute coronary syndrome cases (N=167) were individually matched (1:2) to control patients by sex, age, intervention group, body mass index, and follow-up time. We investigated 2 individual manifestations (myocardial infarction, unstable angina) as secondary outcomes. We measured the following functional characteristics: HDL cholesterol concentration (in plasma); cholesterol efflux capacity; antioxidant ability, measured by the HDL oxidative-inflammatory index; phospholipase A2 activity; and sphingosine-1-phosphate, apolipoproteins A-I and A-IV, serum amyloid A, and complement 3 protein (in apolipoprotein B–depleted plasma). We used conditional logistic regression models adjusted for HDL cholesterol levels and cardiovascular risk factors to estimate odds ratios (ORs) between 1-SD increments in HDL functional characteristics and clinical outcomes. Results: Low values of cholesterol efflux capacity (OR 1SD , 0.58; 95% CI, 0.40–0.83) and low levels of sphingosine-1-phosphate (OR 1SD , 0.70; 95% CI, 0.52–0.92) and apolipoprotein A-I (OR 1SD , 0.58; 95% CI, 0.42–0.79) were associated with higher odds of acute coronary syndrome. Higher HDL oxidative inflammatory index values were marginally linked to acute coronary syndrome risk (OR 1SD , 1.27; 95% CI, 0.99–1.63). Low values of cholesterol efflux capacity (OR 1SD , 0.33; 95% CI, 0.18–0.61), sphingosine-1-phosphate (OR 1SD : 0.60; 95% CI: 0.40–0.89), and apolipoprotein A-I (OR 1SD , 0.59; 95% CI, 0.37–0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR 1SD , 1.53; 95% CI, 1.01–2.33) and low apolipoprotein A-I levels (OR 1SD , 0.52; 95% CI, 0.31–0.88) were associated with unstable angina. Conclusions: Low cholesterol efflux capacity values, pro-oxidant/proinflammatory HDL particles, and low HDL levels of sphingosine-1-phosphate and apolipoprotein A-I were associated with increased odds of acute coronary syndrome and its manifestations in individuals at high cardiovascular risk. Clinical Trial Registration: URL: https://www.controlled-trials.com/ISRCTN35739639 . Unique identifier: ISRCTN35739639.

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Abstract 104: Serum from Patients with Aortic Valvular Stenosis Shows Decreased Cholesterol Efflux Capacities Despite Similar High-Density Lipoprotein Cholesterol Levels

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a104 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Benoit J Arsenault ◽

Mathieu R Brodeur ◽

David Rhainds ◽

Anne-Elen Kernaleguen ◽

Véronique Lavoie ◽

...

Keyword(s):

Cholesterol Efflux ◽

Pearson Correlation ◽

Hdl Cholesterol ◽

P Value ◽

Aortic Valvular Stenosis ◽

Cholesterol Efflux Capacity ◽

Cholesterol Levels ◽

Apolipoprotein A ◽

Valvular Stenosis ◽

Jet Velocity

Background: Studies have shown that low HDL-cholesterol levels may be associated with the progression of aortic valvular calcium and aortic valvular stenosis (AVS), but whether patients with AVS have impaired cholesterol efflux capacities is unknown. Methods and results: We have measured four parameters of cholesterol efflux capacity in apolipoprotein B-depleted serum samples from 48 patients with (aortic jet velocity ≥2.5 m/s, mean age = 72 ± 7 years and 72.7% men) and 51 patients without AVS (aortic jet velocity ≤ 1.7 m/s, mean age 71 ± 7 years and 70.6% men). Cholesterol efflux capacity was measured using J774 macrophages with and without stimulation of ABCA1 expression by cAMP (non-stimulated efflux, total efflux and ABCA1-mediated efflux), and HepG2 hepatocytes to measure SR-BI-mediated efflux. Mean HDL-cholesterol and apolipoprotein A-I levels as well as efflux are shown in the table for patients with vs. without AVS. The Pearson correlation coefficient between HDL-cholesterol levels and SR-B1-dependent efflux was 0.39 (p=0.007) in patients with AVS and 0.68 (<0.0001) in controls (P-value for the difference between the correlation coefficients obtained with Fisher’s test = 0.04). Conclusions: This study provides evidence that serum from patients with AVS may have impaired cholesterol efflux capacities, especially through the SR-B1 pathway. Table. Mean HDL-cholesterol and apolipoprotein A-I levels as well as non-stimulated-, total-, ABCA1-, and SR-B1-dependent cholesterol efflux obtained from patients’ serum with vs. without AVS. Data is shown as mean ± SD. Differences between categories were assessed using a Student unpaired t-test.

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Reactive Dicarbonyl Scavenging Effectively Reduces MPO-Mediated Oxidation of HDL and Preserves HDL Atheroprotective Functions

10.1101/528026 ◽

2019 ◽

Author(s):

Jiansheng Huang ◽

Patricia G. Yancey ◽

Huan Tao ◽

Mark Borja ◽

Loren Smith ◽

...

Keyword(s):

Cholesterol Efflux ◽

Adduct Formation ◽

Paraoxonase 1 ◽

Pon1 Activity ◽

Dependent Manner ◽

Cholesterol Efflux Capacity ◽

Hdl Function ◽

Impaired Ability ◽

Anti Inflammatory ◽

Mediated Oxidation

AbstractHigh-density lipoprotein (HDL) is atheroprotective by mediating cholesterol efflux, anti-inflammatory, and anti-oxidation functions. Atheroprotective functions of HDL are related to the activity of HDL-associated enzymes such as paraoxonase 1 (PON1). We examined the impact of inhibition of myeloperoxidase (MPO)-mediated HDL oxidation by PON1 on HDL malondialdehyde (MDA) content and HDL function. In the presence of PON1, crosslinking of apoAI in response to MPO-mediated oxidation of HDL was abolished and MDA-HDL adduct levels were decreased. In addition, PON1 prevented the impaired cholesterol efflux capacity of MPO-oxidized HDL from Apoe-/- macrophages. Direct modification of HDL with MDA increased apoAI crosslinking and reduced the cholesterol efflux capacity in a dose dependent manner. In addition, MDA modification of HDL reduced its anti-inflammatory function compared to native HDL as the expression of IL-1β and IL6 increased by 3-(p<0.05) and 1.8-fold (p<0.05) in Apoe-/- macrophages in response to LPS. MDA-HDL also had impaired ability to increase PON1 activity. Importantly, HDL from subjects with familial hypercholesterolemia (FH-HDL) versus controls had increased MDA-apoAI adducts, and normalization of the PON1 activity to PON1 mass revealed a 24 % (p<0.05) decrease in specific activity indicating that PON1 activity is also impaired in FH. Consistent with the impaired PON1 activity and increased MDA-apoAI, FH-HDL induced a pro-inflammatory response in Apoe-/- macrophages compared to incubation with LPS alone. FH-HDL versus control HDL also had an impaired ability to promote cholesterol efflux from Apoe-/- macrophages. Interestingly, reactive dicarbonyl scavengers effectively abolished MPO-mediated apoAI crosslinking, MDA adduct formation, and improved cholesterol efflux capacity. Importantly, in vivo treatment of hypercholesterolemic mice with reactive dicarbonyl scavengers effectively reduced MDA-HDL adduct formation and increased PON1 activity and HDL cholesterol efflux capacity, supporting a therapeutic potential of reactive carbonyl scavenging in maintaining HDL function.

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Impaired High‐Density Lipoprotein Function in Patients With Heart Failure

Journal of the American Heart Association ◽

10.1161/jaha.120.019123 ◽

2021 ◽

Author(s):

Johanna E. Emmens ◽

Congzhuo Jia ◽

Leong L. Ng ◽

Dirk J. van Veldhuisen ◽

Kenneth Dickstein ◽

...

Keyword(s):

Heart Failure ◽

Cholesterol Efflux ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Cholesterol Concentration ◽

Hdl Function ◽

Patients With Heart Failure ◽

Hdl Functionality ◽

Anti Inflammatory

Background We recently showed that, in patients with heart failure, lower high‐density lipoprotein (HDL) cholesterol concentration was a strong predictor of death or hospitalization for heart failure. In a follow‐up study, we suggested that this association could be partly explained by HDL proteome composition. However, whether the emerging concept of HDL function contributes to the prognosis of patients with heart failure has not been addressed. Methods and Results We measured 3 key protective HDL function metrics, namely, cholesterol efflux, antioxidative capacity, and anti‐inflammatory capacity, at baseline and after 9 months in 446 randomly selected patients with heart failure from BIOSTAT‐CHF (A Systems Biology Study to Tailored Treatment in Chronic Heart Failure). Additionally, the relationship between HDL functionality and HDL proteome composition was determined in 86 patients with heart failure. From baseline to 9 months, HDL cholesterol concentrations were unchanged, but HDL cholesterol efflux and anti‐inflammatory capacity declined (both P <0.001). In contrast, antioxidative capacity increased ( P <0.001). Higher HDL cholesterol efflux was associated with lower mortality after adjusting for BIOSTAT‐CHF risk models and log HDL cholesterol (hazard ratio, 0.81; 95% CI, 0.71–0.92; P =0.001). Other functionality measures were not associated with outcome. Several HDL proteins correlated with HDL functionality, mainly with cholesterol efflux. Apolipoprotein A1 emerged as the main protein associated with all 3 HDL functionality measures. Conclusions Better HDL cholesterol efflux at baseline was associated with lower mortality during follow‐up, independent of HDL cholesterol. HDL cholesterol efflux and anti‐inflammatory capacity declined during follow‐up in patients with heart failure. Measures of HDL function may provide clinical information in addition to HDL cholesterol concentration in patients with heart failure.

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HDL Cholesterol Efflux Capacity is Impaired in Severe Short-Term Hypothyroidism Despite Increased HDL Cholesterol

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa411 ◽

2020 ◽

Vol 105 (9) ◽

pp. e3355-e3362

Author(s):

Trynke van der Boom ◽

Congzhuo Jia ◽

Joop D Lefrandt ◽

Margery A Connelly ◽

Thera P Links ◽

...

Keyword(s):

Cholesterol Efflux ◽

Particle Concentration ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Antioxidative Capacity ◽

Short Term ◽

Cholesterol Efflux Capacity ◽

Hdl Function ◽

Particle Characteristics ◽

The Impact

Abstract Context Severe hypothyroidism has profound effects on lipoprotein metabolism including high-density lipoprotein (HDL) cholesterol elevations but effects on HDL function metrics are unknown. Objective To determine the impact of severe short-term hypothyroidism on HDL particle characteristics, HDL cholesterol efflux capacity (CEC), and HDL antioxidative capacity. Design Observational study with variables measured during severe short-term hypothyroidism (median TSH 81 mU/L) and after 20 weeks of thyroid hormone supplementation (median TSH 0.03 mU/L) (Netherlands Trial Registry ID 7228). Setting University hospital setting in The Netherlands. Patients Seventeen patients who had undergone a total thyroidectomy for differentiated thyroid carcinoma. Main outcome measures HDL particle characteristics (nuclear magnetic resonance spectrometry), CEC (human THP-1-derived macrophage foam cells and apolipoprotein B-depleted plasma), and HDL anti-oxidative capacity (inhibition of low-density lipoprotein oxidation). Results During hypothyroidism plasma total cholesterol, HDL cholesterol and apolipoprotein A-I were increased (P ≤ 0.001). HDL particle concentration was unchanged, but there was a shift in HDL subclasses toward larger HDL particles (P < 0.001). CEC was decreased (P = 0.035), also when corrected for HDL cholesterol (P < 0.001) or HDL particle concentration (P = 0.011). HDL antioxidative capacity did not change. Conclusion During severe short-term hypothyroidism CEC, an important antiatherogenic metric of HDL function, is impaired. HDL cholesterol and larger HDL particles are increased but HDL particle concentration is unchanged. Combined, these findings suggest that HDL quality and quantity are not improved, reflecting dysfunctional HDL in hypothyroidism.

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Prolonged bedrest reduces plasma high-density lipoprotein levels linked to markedly suppressed cholesterol efflux capacity

Scientific Reports ◽

10.1038/s41598-020-71921-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Athina Trakaki ◽

Hubert Scharnagl ◽

Markus Trieb ◽

Michael Holzer ◽

Helmut Hinghofer-Szalkay ◽

...

Keyword(s):

Cholesterol Efflux ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Oxidative Capacity ◽

High Density ◽

High Density Lipoproteins ◽

Cholesterol Efflux Capacity ◽

Vibration Exercise ◽

Amyloid A ◽

Hdl Function

Abstract Recent observations strongly connect high-density lipoproteins (HDL) function and levels with coronary heart disease outcomes and risk for infections and sepsis. To date, our knowledge of factors determining this connection is still very limited. The immobility associated with prolonged bedrest is detrimental to health, affecting several systems, including the cardiovascular, pulmonary, gastrointestinal, musculoskeletal and urinary. Effects of prolonged bedrest on the composition and functional properties of HDL remain elusive. We evaluated metrics of HDL composition and function in healthy male volunteers participating in a randomized, crossover head-down bedrest study. We observed that HDL cholesterol efflux capacity was profoundly decreased during bedrest, mediated by a bedrest associated reduction in plasma levels of HDL-cholesterol and major apolipoproteins (apo) apoA-I and apoA-II. Paraoxonase activity, plasma anti-oxidative capacity and the activities of lecithin-cholesterol acyltransferase and cholesteryl ester transfer protein were not affected. No change was observed in the content of HDL-associated serum amyloid A, a sensitive marker of inflammation. Resistive vibration exercise countermeasure during bedrest did not correct impaired cholesterol efflux capacity and only tended to increase arylesterase activity of HDL-associated paraoxonase. In conclusion, prolonged bedrest reduces plasma HDL levels linked to markedly suppressed HDL cholesterol efflux capacity. Resistive vibration exercise during bedrest did not correct HDL levels and impaired cholesterol efflux capacity.

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Reactive Dicarbonyl Scavenging Effectively Reduces MPO-Mediated Oxidation of HDL and Restores PON1 Activity

Nutrients ◽

10.3390/nu12071937 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1937 ◽

Cited By ~ 1

Author(s):

Jiansheng Huang ◽

Patricia G. Yancey ◽

Huan Tao ◽

Mark S. Borja ◽

Loren E. Smith ◽

...

Keyword(s):

Cholesterol Efflux ◽

Adduct Formation ◽

Paraoxonase 1 ◽

High Density Lipoproteins ◽

Pon1 Activity ◽

Cholesterol Efflux Capacity ◽

Hdl Function ◽

Impaired Ability ◽

The Impact ◽

Mediated Oxidation

Atheroprotective functions of high-density lipoproteins (HDL) are related to the activity of HDL-associated enzymes such as paraoxonase 1 (PON1). We examined the impact of inhibition of myeloperoxidase (MPO)-mediated HDL oxidation by PON1 on HDL malondialdehyde (MDA) content and HDL function. In the presence of PON1, crosslinking of apoAI in response to MPO-mediated oxidation of HDL was abolished, and MDA-HDL adduct levels were decreased. PON1 prevented the impaired cholesterol efflux capacity of MPO-oxidized HDL from Apoe−/− macrophages. Direct modification of HDL with MDA increased apoAI crosslinking and reduced the cholesterol efflux capacity. MDA modification of HDL reduced its anti-inflammatory function compared to native HDL. MDA-HDL also had impaired ability to increase PON1 activity. Importantly, HDL from subjects with familial hypercholesterolemia (FH-HDL) versus controls had increased MDA-apoAI adducts, and PON1 activity was also impaired in FH. Consistently, FH-HDL induced a pro-inflammatory response in Apoe−/− macrophages and had an impaired ability to promote cholesterol efflux. Interestingly, reactive dicarbonyl scavengers, including 2-hydroxybenzylamine (2-HOBA) and pentyl-pyridoxamine (PPM), effectively abolished MPO-mediated apoAI crosslinking, MDA adduct formation, and improved cholesterol efflux capacity. Treatment of hypercholesterolemic mice with reactive dicarbonyl scavengers reduced MDA-HDL adduct formation and increased HDL cholesterol efflux capacity, supporting the therapeutic potential of reactive carbonyl scavenging for improving HDL function.

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