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

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.

SUBMITTER: Huang J

PROVIDER: S-EPMC7400685 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Huang Jiansheng J Yancey Patricia G PG Tao Huan H Borja Mark S MS Smith Loren E LE Kon Valentina V Davies Sean S SS Linton MacRae F MF

Nutrients 20200630 7

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 o ...[more]

PMID: 32629758

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Project description:PurposeTo 1) evaluate the clinical efficacy of arthroscopic posterior capsular release for improving range of motion (ROM) in cases of recalcitrant flexion contracture and 2) determine patient-reported outcomes (PROs) postoperatively.MethodsRetrospective chart review was performed to identify patients who underwent arthroscopic posterior capsular release due to persistent extension deficit of the knee despite comprehensive nonoperative physical therapy between 2008 and 2021. Knee ROM and PROs (International Knee Documentation Committee [IKDC], Tegner, and visual analog scale [VAS]) were collected at final follow-up.ResultsOverall, 22 patients were included with a median age of 37 years (interquartile range [IQR]: 20.5-44.3). Of these, 8 (36%) were male and 14 (64%) were female, and average follow-up was 3.7 ± 3.3 years. The most common etiology was knee flexion contracture after anterior cruciate ligament (ACL) reconstruction (59%). All patients failed a minimum of 3 months of nonoperative management. Prior to operative intervention, 100% of patients received physical therapy, 64% received extension knee bracing or casting, and 36% received corticosteroid injection. Median preoperative extension was 15° (IQR: 10-25) compared to 2° (IQR: 0-5) postoperatively (P < .001). At final follow-up, median extension was 0° (IQR: 0-3.5). Postoperative VAS pain scores at rest (2 vs 0; P = .001) and with use (5 vs 1.8; P = .017) improved at final contact, and most (94%) patients reported maintaining their extension ROM. Patients with ACL-related extension deficit reported better IKDC (81 vs 51.3; P = .008), Tegner (5.8 vs 3.6; P = .007), and VAS pain scores (rest: 0.2 vs 1.8; P = .008; use: 1.3 vs 5; P = .004) compared to other etiologies.ConclusionArthroscopic posterior capsular release for recalcitrant flexion contracture provides an effective means for reducing pain and restoring terminal extension. The improvement in extension postoperatively was maintained for most (94%) patients at final follow-up with a 14% reoperation rate.

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Dataset Information

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

Publications

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

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