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

Jiansheng Huang,Sean S Davies,Mark S Borja,Patricia G Yancey,Valentina Kon,Huan Tao,Loren E Smith,Macrae F Linton

doi:10.3390/nu12071937

Abstract

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.

Highlights

Familial hypercholesterolemia (FH) is an autosomal dominant disorder, most commonly due to mutations in the genes for LDLR, ApoB and PCSK9, characterized by remarkably increased levels of low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary artery disease [1].Nutrients 2020, 12, 1937; doi:10.3390/nu12071937 www.mdpi.com/journal/nutrientsThe high risk of premature cardiovascular disease (CVD) is attributable to the increased levels of LDL-C and oxidized LDL, with little attention paid to the role of high-density lipoproteins (HDL) function.The relationship between HDL-C levels and risk for atherothrombosis is complex, as there are apparent exceptions to the inverse relationship at both ends of the HDL-C spectrum [2]
We examined the impact of HDL-associated paraoxonase 1 (PON1) in preventing MPO-mediated HDL MDA modification and dysfunction, and the potential role of reduced PON1 activity in promoting increased MDA modification and impaired function of HDL in FH patients
MPO increased the production of MDA-HDL adducts seven-fold (p < 0.05) compared to the MDA content of HDL not treated with MPO (Figure 2C)

Summary

Introduction

Familial hypercholesterolemia (FH) is an autosomal dominant disorder, most commonly due to mutations in the genes for LDLR, ApoB and PCSK9, characterized by remarkably increased levels of low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary artery disease [1].Nutrients 2020, 12, 1937; doi:10.3390/nu12071937 www.mdpi.com/journal/nutrientsThe high risk of premature cardiovascular disease (CVD) is attributable to the increased levels of LDL-C and oxidized LDL, with little attention paid to the role of high-density lipoproteins (HDL) function.The relationship between HDL-C levels and risk for atherothrombosis is complex, as there are apparent exceptions to the inverse relationship at both ends of the HDL-C spectrum [2]. Familial hypercholesterolemia (FH) is an autosomal dominant disorder, most commonly due to mutations in the genes for LDLR, ApoB and PCSK9, characterized by remarkably increased levels of low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary artery disease [1]. The high risk of premature cardiovascular disease (CVD) is attributable to the increased levels of LDL-C and oxidized LDL, with little attention paid to the role of high-density lipoproteins (HDL) function. Recent evidence suggests that HDL particle number may be a better gauge than HDL-C levels for CVD protection. Recent studies have shown that HDL cholesterol efflux capacity is inversely associated with carotid and coronary atherosclerosis and atherosclerotic cardiovascular events independent of HDL-C levels [3,4,5,6].

Methods

Results

Discussion

Conclusion