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Febuxostat, a Xanthine Oxidase Inhibitor, Decreased Macrophage Matrix Metalloproteinase Expression in Hypoxia.

ABSTRACT: Macrophages in the atheroma region produce matrix metalloproteinases (MMPs) and decrease plaque stability. Tissue oxygen tension decreases in the arterial wall of the atherosclerotic region. Hypoxia inducible factor (HIF)-1? plays a critical role in the transcriptional activation of hypoxia inducible genes. However, the precise roles of HIF-1? independent pathways in hypoxic responses are largely unknown. Xanthine oxidase (XO) is an enzyme that utilizes molecular oxygen and produces reactive oxygen species (ROS). Here, we show that ROS derived from XO increases MMP-3, -10, and -13 expression in murine macrophages. We found that the transcript levels of macrophage MMP-3, -10, and -13 were increased in hypoxic conditions. Hypoxia induced MMP expression in HIF-1? deficient macrophages. N-acetylcysteine (NAC) or febuxostat, an XO inhibitor, suppressed MMP expression in murine macrophages. Febuxostat decreased the incidence of plaque rupture in apolipoprotein-E-deficient mice. Our results indicate that febuxostat stabilized atherosclerotic plaque via suppressing the activities of macrophage MMP-9 and -13. Febuxostat administration is a potential therapeutic option in the management of atherosclerotic patients.

SUBMITTER: Wei S

PROVIDER: S-EPMC7693746 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Febuxostat, a Xanthine Oxidase Inhibitor, Decreased Macrophage Matrix Metalloproteinase Expression in Hypoxia.

Wei Shuoyu S Isagawa Takayuki T Eguchi Masamichi M Sato Daisuke D Tsukano Hiroto H Miyata Keishi K Oike Yuichi Y Takeda Norihiko N Ikeda Satoshi S Kawano Hiroaki H Maemura Koji K

Biomedicines 20201103 11

Macrophages in the atheroma region produce matrix metalloproteinases (MMPs) and decrease plaque stability. Tissue oxygen tension decreases in the arterial wall of the atherosclerotic region. Hypoxia inducible factor (HIF)-1α plays a critical role in the transcriptional activation of hypoxia inducible genes. However, the precise roles of HIF-1α independent pathways in hypoxic responses are largely unknown. Xanthine oxidase (XO) is an enzyme that utilizes molecular oxygen and produces reactive oxy ...[more]

PMID: 33153000

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Project description:BACKGROUND:Clinacanthus nutans (Burm. f.) Lindau has gained popularity among Malaysians as a traditional plant for anti-inflammatory activity. OBJECTIVE:This prompted us to carry out the present study on a selected 11 constituents of C. nutans which are clinacoside A-C, cycloclinacoside A1, shaftoside, vitexin, orientin, isovitexin, isoorientin, lupeol and ?-sitosterol. MATERIALS AND METHODS:Selected 11 constituents of C. nutans were evaluated on the docking behavior of xanthine oxidase (XO), nitric oxide synthase (NOS), human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and 9), and squalene synthase (SQS) using Discovery Studio Version 3.1. Also, molecular physicochemical, bioactivity, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and toxicity prediction by computer assisted technology analyzes were also carried out. RESULTS:The molecular physicochemical analysis revealed that four ligands, namely clinacoside A-C and cycloclinacoside A1 showed nil violations and complied with Lipinski's rule of five. As for the analysis of bioactivity, all the 11 selected constituents of C. nutans exhibited active score (>0) toward enzyme inhibitors descriptor. ADMET analysis showed that the ligands except orientin and isoorientin were predicted to have Cytochrome P4502D6 inhibition effect. Docking studies and binding free energy calculations revealed that clinacoside B exhibited the least binding energy for the target enzymes except for XO and SQS. Isovitexin and isoorientin showed the potentials in the docking and binding with all of the six targeted enzymes, whereas vitexin and orientin docked and bound with only NOS and HNE. CONCLUSION:This present study has paved a new insight in understanding these 11 C. nutans ligands as potential inhibitors against XO, NOS, HNE, MMP 2, MMP 9, and SQS. SUMMARY:Isovitexin and isoorientin (Clinacanthus nutans constituent) showed potentials in the docking and binding with all of the six targeted enzymes (xanthine oxidase [XO], nitric oxide synthase [NOS], human neutrophil elastase [HNE], matrix metalloproteinase [MMP 2 and 9], and squalene synthase [SQS])Moreover, clinacoside B (C. nutans constituent) exhibited the least binding energy for the target enzymes except for XO and SQSInterestingly, all of the selected ligands from C. nutans showed the potential to dock and bind with HNE. Abbreviations used: C. nutans: Clinacanthus nutans, XO: Xanthine oxidase, NOS: Nitric oxide synthase, HNE: Human neutrophil elastase, MMP: Matrix metalloproteinase, SQS: Squalene synthase, ADMET: Absorption, Distribution, Metabolism, Excretion, and Toxicity, TOPKAT: Toxicity prediction by the computer assisted technology.

Project description:Rationale: The pathophysiologic mechanisms by which World Trade Center (WTC) dust exposure leads to pulmonary disease have not been established. Matrix metalloproteinase-12 (MMP-12) is involved in the development of pulmonary fibrosis and chronic obstructive pulmonary disease. We have previously shown that exposure of mice to WTC dust results in increased expression of matrix metalloproteinase 12 by alveolar macrophages. Matrix metalloproteinase 12 expression is regulated, in part, by oxidative stress, which is also increased after WTC dust exposure. A significant percentage of WTC dust–exposed individuals have concomitant obstructive sleep apnea, which is an added source of oxidative stress, through chronic intermittent hypoxia (CIH). Objectives: To determine if combined exposures of mice to WTC dust and CIH exacerbated matrix metalloproteinase 12 expression in alveolar macrophages. Methods: Male Balbc/J mice (12–24 wk) were treated intratracheally with phosphate-buffered saline (PBS) or WTC dust suspended in PBS, followed by CIH (cycles of 21 to 5% fraction of inspired oxygen, 2-min cycles) (CIH groups) or chronic intermittent air (CIA; cycles of 21 to 19% fraction of inspired oxygen, 2-min cycles) (CIA groups) 12 hours per day for 28 days. Histologic sections were then examined for macrophage expression of matrix metalloproteinase 12 by immunohistochemistry. Results: The mean number of positively stained alveolar macrophages from five fields per lobe was quantified. Mice exposed to WTC dust or CIH displayed increased macrophage expression of matrix metalloproteinase 12 compared with the control group. Exposure to WTC dust plus CIH was additive in effect (mean?±?SD, PBS/CIA: 20.8?±?5.2; PBS/CIH: 43.3?±?19.8; WTC/CIA: 43.3?±?12.5; WTC/CIH: 77.8?±?12.2). Conclusions: To our knowledge, this is the first study to suggest CIH increases macrophage matrix metalloproteinase 12 expression in mice. Combined exposures to WTC dust and CIH further increased macrophage matrix metalloproteinase 12 expression. Given the role of matrix metalloproteinase 12 in pulmonary fibrosis and chronic obstructive pulmonary disease pathogenesis, patients with obstructive sleep apnea who have been exposed to WTC dust may have added risk for pulmonary parenchymal disease.

Dataset Information

Febuxostat, a Xanthine Oxidase Inhibitor, Decreased Macrophage Matrix Metalloproteinase Expression in Hypoxia.

Publications

Febuxostat, a Xanthine Oxidase Inhibitor, Decreased Macrophage Matrix Metalloproteinase Expression in Hypoxia.

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