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

Autor:	Huang J; Department of Medicine, Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Yancey PG; Department of Medicine, Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Tao H; Department of Medicine, Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Borja MS; Department of Chemistry & Biochemistry, California State University East Bay, Hayward, CA 94542, USA., Smith LE; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Kon V; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Davies SS; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA., Linton MF; Department of Medicine, Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University Medical Center, Nashville, TN 37232, USA.; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
Jazyk:	angličtina
Zdroj:	Nutrients [Nutrients] 2020 Jun 30; Vol. 12 (7). Date of Electronic Publication: 2020 Jun 30.
DOI:	10.3390/nu12071937
Abstrakt:	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. Competing Interests: With regard to potential conflicts of interest, Linton and Davies are inventors on a patent application for the use of 2-HOBA and related dicarbonyl scavengers for the treatment of cardiovascular disease. All other authors declare no financial conflicts of interest.
Databáze:	MEDLINE
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