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Open AccessArticle

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

1
Department of Medicine, Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University Medical Center, Nashville, TN 37232, USA
2
Department of Chemistry & Biochemistry, California State University East Bay, Hayward, CA 94542, USA
3
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
4
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
5
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
*
Author to whom correspondence should be addressed.
Nutrients 2020, 12(7), 1937; https://doi.org/10.3390/nu12071937
Received: 24 April 2020 / Revised: 10 June 2020 / Accepted: 23 June 2020 / Published: 30 June 2020
(This article belongs to the Special Issue Lipid Metabolism in Inflammation and Immune Function)
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.
Keywords: high-density lipoprotein (HDL), malondialdehyde (MDA), reactive dicarbonyl scavengers; inflammation; cholesterol efflux; macrophages; familial hypercholesterolemia high-density lipoprotein (HDL), malondialdehyde (MDA), reactive dicarbonyl scavengers; inflammation; cholesterol efflux; macrophages; familial hypercholesterolemia
MDPI and ACS Style

Huang, J.; Yancey, P.G.; Tao, H.; Borja, M.S.; Smith, L.E.; Kon, V.; Davies, S.S.; Linton, M.F. Reactive Dicarbonyl Scavenging Effectively Reduces MPO-Mediated Oxidation of HDL and Restores PON1 Activity. Nutrients 2020, 12, 1937.

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