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Tian R, Yang YD, Lu N. Epigallocatechin-3-gallate as an effective inhibitor of vascular endothelial dysfunction induced by endothelial-localized myeloperoxidase. Food Chem Toxicol 2025; 200:115392. [PMID: 40086586 DOI: 10.1016/j.fct.2025.115392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/16/2024] [Accepted: 03/11/2025] [Indexed: 03/16/2025]
Abstract
In inflammatory vasculature, the leukocyte-released myeloperoxidase (MPO) is internalized by endothelial cells and this enzyme promotes endothelial dysfunction by catalytically producing strong oxidant, hypochlorous acid (HOCl). Herein, we developed epigallocatechin-3-gallate (EGCG, the main polyphenolic flavonoid found in green tea) as a novel endothelial-targeted MPO inhibitor. It was shown that culture of MPO and EGCG with vascular endothelial cells could result in their transport into the sub-endothelial space. EGCG significantly suppressed the consumption of enzyme's substrate H2O2 and generation of HOCl catalyzed by endothelial-transcytosed MPO. The binding of EGCG to the hydrophobic domain near the distal active heme cavity of enzyme was proposed by molecular docking and was suggested for the inhibitive effect of flavonoid on MPO activity. In vivo, EGCG attenuated lipopolysaccharide (LPS)-induced endothelial dysfunction in mouse aortas, while it inhibited the infiltration of active MPO into vascular walls. Furthermore, MPO-deficient mice were resistant to the protective effects of EGCG on LPS-induced vascular dysfunction, as compared to wild-type mice. These studies showed that EGCG effectively inhibited local oxidative reactions and endothelial dysfunction catalyzed by vascular-bound MPO. EGCG represents a versatile class of natural antioxidant drugs applicable to target endothelial-transcytosed MPO in inflammatory vasculature.
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Affiliation(s)
- Rong Tian
- College of Chemistry and Materials, Key Laboratory of Green Catalysis of Jiangxi Education Institutes, Jiangxi Normal University, Nanchang, 330022, China
| | - Ya-Di Yang
- College of Chemistry and Materials, Key Laboratory of Green Catalysis of Jiangxi Education Institutes, Jiangxi Normal University, Nanchang, 330022, China
| | - Naihao Lu
- College of Chemistry and Materials, Key Laboratory of Green Catalysis of Jiangxi Education Institutes, Jiangxi Normal University, Nanchang, 330022, China.
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2
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Cai Y, Yang Q, Tang X, Wang P, Cui J, Du X, Zhang T, Chen Y. Baicalin mitigates hyperglycemia-linked intestinal epithelial barrier impairment in part by inhibiting the formation of neutrophil extracellular traps. Front Immunol 2025; 16:1551256. [PMID: 40098957 PMCID: PMC11911346 DOI: 10.3389/fimmu.2025.1551256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 02/14/2025] [Indexed: 03/19/2025] Open
Abstract
Background Under hyperglycemic conditions, impaired intestinal barrier integrity leads to heightened level of inflammation, playing important roles in driving diabetic complications. Emerging evidence supports the implications of neutrophil extracellular traps (NETs) in the pathogenesis of diabetes. However, whether NETs contribute to hyperglycemia-linked intestinal barrier impairment remains to be investigated. Moreover, baicalin, the major chemical component of Scutellaria baicalensis Georgi, is equipped with twofold intestinal protective and neutrophil suppressive activities. Yet, it is unclear if baicalin is effective at mitigating hyperglycemia-linked NETs-mediated intestinal barrier impairment. Methods To directly address the mechanistic implications of NETs in hyperglycemia-linked intestinal epithelial barrier impairment, the impact of DNase I treatment or Padi4 gene deficiency on intestinal epithelial integrity was first examined in the streptozotocin (STZ)-induced hyperglycemic mice in vivo. Next, the pharmacological impact of baicalin on NETs formation and intestinal epithelial barrier impairment was investigated in high glucose- and/or lipopolysaccharides (LPS)-stimulated neutrophils in vitro and in STZ-induced hyperglycemic mice in vivo, respectively. Results The in vitro experiments confirmed that high glucose and/or LPS induced NETs formation. NETs directly impaired the viability and tight junction of the intestinal epithelial cells. The histological and immunohistochemical examinations unveiled that along with impaired intestinal epithelial morphology, citrullinated histone H3 (H3Cit), a marker of NETs, and neutrophil specific Ly6G were readily detected in the intestinal epithelium in the hyperglycemic mice. Without affecting the presence of neutrophils, DNase I treatment or Padi4 gene deficiency markedly mitigated intestinal NETs formation and improved the intestinal morphology in the hyperglycemic mice. Notably, baicalin suppressed NETs formation and inhibited histone H3 citrullination stimulated by high glucose, LPS or both in vitro. Furthermore, baicalin blunted NETs formation and partially preserved the integrity of the intestinal epithelium in the hyperglycemic mice in vivo. Conclusions The current study sheds new light on the pathophysiological implications of NETs in intestinal epithelial barrier impairment under hyperglycemic conditions. Most importantly, the findings here demonstrate for the first time that baicalin directly inhibits NETs formation stimulated by high glucose and/or LPS, which may in part account for its pharmacological effects at protecting against hyperglycemia-linked intestinal epithelial barrier impairment.
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Affiliation(s)
- Yiqing Cai
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qinbo Yang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Clinical Research Institute of Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Xinmiao Tang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Peiwei Wang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Clinical Research Institute of Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Jingang Cui
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Clinical Research Institute of Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoye Du
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Clinical Research Institute of Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Teng Zhang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Clinical Research Institute of Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Yu Chen
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Clinical Research Institute of Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Laboratory of Clinical and Molecular Pharmacology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Brown AP, Friedrichs GS, Tang HM, Traebert M, Weber V, Yao N, Yan GX. Electrophysiological Changes in the Rabbit Ventricular Wedge and Human-Induced Pluripotent Stem-Cell Derived (IPSC) Cardiomyocytes Translate to Severe Arrhythmia Observed in a Canine Toxicology Study, Not Predicted by Standard In Vitro Ion Channel Assays. Int J Toxicol 2024; 43:231-242. [PMID: 38327194 DOI: 10.1177/10915818241230900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
During drug discovery, small molecules are typically assayed in vitro for secondary pharmacology effects, which include ion channels relevant to cardiac electrophysiology. Compound A was an irreversible inhibitor of myeloperoxidase investigated for the treatment of peripheral artery disease. Oral doses in dogs at ≥5 mg/kg resulted in cardiac arrhythmias in a dose-dependent manner (at Cmax, free ≥1.53 μM) that progressed in severity with time. Nevertheless, a panel of 13 different cardiac ion channel (K, Na, and Ca) assays, including hERG, failed to identify pharmacologic risks of the molecule. Compound A and a related Compound B were evaluated for electrophysiological effects in the isolated rabbit ventricular wedge assay. Compounds A and B prolonged QT and Tp-e intervals at ≥1 and ≥.3 μM, respectively, and both prolonged QRS at ≥5 μM. Compound A produced early after depolarizations and premature ventricular complexes at ≥5 μM. These data indicate both compounds may be modulating hERG (Ikr) and Nav1.5 ion channels. In human IPSC cardiomyocytes, Compounds A and B prolonged field potential duration at ≥3 μM and induced cellular dysrhythmia at ≥10 and ≥3 μM, respectively. In a rat toxicology study, heart tissue: plasma concentration ratios for Compound A were ≥19X at 24 hours post-dose, indicating significant tissue distribution. In conclusion, in vitro ion channel assays may not always identify cardiovascular electrophysiological risks observed in vivo, which can be affected by tissue drug distribution. Risk for arrhythmia may increase with a "trappable" ion channel inhibitor, particularly if cardiac tissue drug levels achieve a critical threshold for pharmacologic effects.
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Affiliation(s)
- Alan P Brown
- Novartis Biomedical Research, Cambridge, MA, USA
| | | | | | | | | | - Nancy Yao
- Novartis Biomedical Research, East Hanover, NJ, USA
| | - Gan-Xin Yan
- Lankenau Institute for Medical Research, Wynnewood, PA, USA
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4
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Souza ACD, Silva DGD, Jezuíno JDS, Ferreira ARO, Ribeiro MVG, Vidigal CB, Moura KF, Erthal RP, Mathias PCDF, Fernandes GSA, Palma-Rigo K, Ceravolo GS. Protein restriction during peripubertal period impairs endothelial aortic function in adult male Wistar rats. J Dev Orig Health Dis 2023; 14:451-458. [PMID: 37198976 DOI: 10.1017/s2040174423000119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Protein restriction during early phases of body development, such as intrauterine life can favor the development of vascular disorders. However, it is not known if peripubertal protein restriction can favor vascular dysfunction in adulthood. The present study aimed to evaluated whether a protein restriction diet during peripubertal period favors endothelial dysfunction in adulthood. Male Wistar rats from postnatal day (PND) 30 until 60 received a diet with either 23% protein (CTR group) or with 4% protein (LP group). At PND 120, the thoracic aorta reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was evaluated in the presence or absence of: endothelium, indomethacin, apocynin and tempol. The maximum response (Rmax) and pD2 (-log of the concentration of the drug that causes 50% of the Rmax) were calculated. The lipid peroxidation and catalase activity were also evaluated in the aorta. The data were analyzed by ANOVA (one or two-ways and Tukey's) or independent t-test; the results were expressed as mean ± S.E.M., p < 0.05. The Rmax to phenylephrine in aortic rings with endothelium were increased in LP rats when compared with the Rmax in CTR rats. Apocynin and tempol reduced Rmax to phenylephrine in LP aortic rings but not in CTR. The aortic response to the vasodilators was similar between the groups. Aortic catalase activity was lower and lipid peroxidation was greater in LP compared to CTR rats. Therefore, protein restriction during the peripubertal period causes endothelial dysfunction in adulthood through a mechanism related to oxidative stress.
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Affiliation(s)
- Amanda Cristina de Souza
- Department of Physiological Sciences, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
| | - Deborah Gomes da Silva
- Graduation Program of Physiological Sciences, Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
| | - Juliana da Silva Jezuíno
- Department of Physiological Sciences, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
| | - Anna Rebeka Oliveira Ferreira
- Department of Cell Biology and Genetics, Center of Biological Sciences, State University of Maringa, Maringa, Brazil
| | - Maiara Vanusa Guedes Ribeiro
- Department of Cell Biology and Genetics, Center of Biological Sciences, State University of Maringa, Maringa, Brazil
| | - Camila Borecki Vidigal
- Department of Physiological Sciences, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
| | - Kawane Fabricio Moura
- Graduation Program of Physiological Sciences, Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
| | - Rafaela Pires Erthal
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
| | | | - Glaura Scantamburlo Alves Fernandes
- Graduation Program of Physiological Sciences, Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
| | - Kesia Palma-Rigo
- Department of Cell Biology and Genetics, Center of Biological Sciences, State University of Maringa, Maringa, Brazil
- Adventist College of Parana, Ivatuba, Brazil
| | - Graziela Scalianti Ceravolo
- Department of Physiological Sciences, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
- Graduation Program of Physiological Sciences, Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
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Li JX, Tian R, Lu N. Quercetin Attenuates Vascular Endothelial Dysfunction in Atherosclerotic Mice by Inhibiting Myeloperoxidase and NADPH Oxidase Function. Chem Res Toxicol 2023; 36:260-269. [PMID: 36719041 DOI: 10.1021/acs.chemrestox.2c00334] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Myeloperoxidase (MPO) exhibits a unique property to use H2O2 to oxidize chloride and lead to the generation of a strong oxidant, hypochlorous acid (HOCl), which plays important roles in atherosclerosis. A lot of evidence indicates that quercetin, a natural polyphenol derived from human diet, effectively contributes to cardiovascular health. Herein, we found that dietary quercetin significantly inhibited vascular endothelial dysfunction and atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Mechanistic studies revealed that dietary quercetin effectively suppressed the MPO level and activity in the vessels of ApoE-/- animals, and p47phox expression and NADPH oxidase activity were simultaneously attenuated after quercetin treatment. In vascular endothelial cells, NADPH oxidase was demonstrated to be the major source of H2O2 formation. Moreover, quercetin effectively attenuated MPO/H2O2-mediated HOCl production and toxicity to human vascular endothelial cells, and this compound was not toxic. The inhibitory effect on MPO activity was likely attributed to that quercetin significantly inhibited NADPH oxidase-derived H2O2 formation in human endothelial cells and could act as an effective mediator for MPO intermediates, subsequently preventing HOCl production by the MPO/H2O2 system. Collectively, it was suggested that quercetin effectively suppressed endothelial dysfunction in atherosclerotic vasculature through the reduction of MPO/NADPH oxidase-mediated HOCl production.
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Affiliation(s)
- Jia-Xin Li
- College of Chemistry and Chemical Engineering, Jiangxi Key Laboratory of Green Chemistry, Jiangxi Normal University, Ziyang Road 99, Nanchang, Jiangxi 330022, China
| | - Rong Tian
- College of Chemistry and Chemical Engineering, Jiangxi Key Laboratory of Green Chemistry, Jiangxi Normal University, Ziyang Road 99, Nanchang, Jiangxi 330022, China
| | - Naihao Lu
- College of Chemistry and Chemical Engineering, Jiangxi Key Laboratory of Green Chemistry, Jiangxi Normal University, Ziyang Road 99, Nanchang, Jiangxi 330022, China
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Murotomi K, Umeno A, Shichiri M, Tanito M, Yoshida Y. Significance of Singlet Oxygen Molecule in Pathologies. Int J Mol Sci 2023; 24:ijms24032739. [PMID: 36769060 PMCID: PMC9917472 DOI: 10.3390/ijms24032739] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/22/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
Reactive oxygen species, including singlet oxygen, play an important role in the onset and progression of disease, as well as in aging. Singlet oxygen can be formed non-enzymatically by chemical, photochemical, and electron transfer reactions, or as a byproduct of endogenous enzymatic reactions in phagocytosis during inflammation. The imbalance of antioxidant enzymes and antioxidant networks with the generation of singlet oxygen increases oxidative stress, resulting in the undesirable oxidation and modification of biomolecules, such as proteins, DNA, and lipids. This review describes the molecular mechanisms of singlet oxygen production in vivo and methods for the evaluation of damage induced by singlet oxygen. The involvement of singlet oxygen in the pathogenesis of skin and eye diseases is also discussed from the biomolecular perspective. We also present our findings on lipid oxidation products derived from singlet oxygen-mediated oxidation in glaucoma, early diabetes patients, and a mouse model of bronchial asthma. Even in these diseases, oxidation products due to singlet oxygen have not been measured clinically. This review discusses their potential as biomarkers for diagnosis. Recent developments in singlet oxygen scavengers such as carotenoids, which can be utilized to prevent the onset and progression of disease, are also described.
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Affiliation(s)
- Kazutoshi Murotomi
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8566, Japan
| | - Aya Umeno
- Department of Ophthalmology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan
| | - Mototada Shichiri
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ikeda 563-8577, Japan
- Correspondence: ; Tel.: +81-72-751-8234
| | - Masaki Tanito
- Department of Ophthalmology, Shimane University Faculty of Medicine, Izumo 693-8501, Japan
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7
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Weng M, Yue Y, Wu D, Zhou C, Guo M, Sun C, Liao Q, Sun M, Zhou D, Miao C. Increased MPO in Colorectal Cancer Is Associated With High Peripheral Neutrophil Counts and a Poor Prognosis: A TCGA With Propensity Score-Matched Analysis. Front Oncol 2022; 12:940706. [PMID: 35912260 PMCID: PMC9331745 DOI: 10.3389/fonc.2022.940706] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/09/2022] [Indexed: 12/26/2022] Open
Abstract
Background Myeloperoxidase (MPO) has been demonstrated to be a local mediator of inflammation in tissue damage in various inflammatory diseases. Given its controversial effect on colorectal cancer (CRC), there has been growing interest in investigating the role of this enzyme in CRC. The mechanism underlying MPO activity and CRC progression requires further clarification. Methods The expression and function of MPO in CRC were evaluated using TCGA analysis. TCGA, TIMER, and Human Cell Landscape analyses were used to analyze the correlation between MPO expression and neutrophil infiltration in CRC. Spearman's bivariate correlation analysis was used to verify the correlation between MPO levels in CRC and the peripheral neutrophil count. In the clinical analysis, 8,121 patients who underwent elective surgery for CRC were enrolled in this retrospective cohort study from January 2008 to December 2014. Propensity score matching was used to address the differences in baseline characteristics. The Kaplan-Meier method and Cox regression analysis were used to identify independent prognostic factors in patients with CRC. Results MPO was upregulated in CRC tissues, which is related to malignant progression and worse survival in CRC patients from TCGA analysis. MPO was significantly correlated with the infiltration level of neutrophils in CRC in TCGA, TIMER, and Human Cell Landscape analyses. MPO was positively correlated with the peripheral neutrophil count. Data of the 8,121 patients who underwent CRC surgery were available for analysis. After propensity score matching, 3,358 patients were included in each group. Kaplan-Meier survival curves showed that high preoperative neutrophil levels were associated with decreased overall survival (OS; P < 0.001) and disease-free survival (DFS; P = 0.015). The preoperative neutrophil count was an independent risk factor for OS (hazard ratio [HR], 1.157; 95% confidence interval [CI], 1.055-1.268; P = 0.002) and DFS (HR, 1.118; 95% CI, 1.009-1.238; P = 0.033). Conclusions Our research indicates that increased MPO levels in CRC are significantly correlated with high preoperative neutrophil counts, and both serve as prognostic indicators for worse survival in CRC patients. Our study suggests that neutrophils may be key players in the mechanism linking MPO levels with poor CRC outcomes.
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Affiliation(s)
- Meilin Weng
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying Yue
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dan Wu
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Changming Zhou
- Department of Cancer Prevention, Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Miaomiao Guo
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Caihong Sun
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qingwu Liao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Minli Sun
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Di Zhou
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Changhong Miao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
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Jing Cao, Zhang G, Liu Z, Xu Q, Li C, Cheng G, Shi R. Peroxidasin promotes diabetic vascular endothelial dysfunction induced by advanced glycation end products via NOX2/HOCl/Akt/eNOS pathway. Redox Biol 2021; 45:102031. [PMID: 34116361 PMCID: PMC8192873 DOI: 10.1016/j.redox.2021.102031] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 05/14/2021] [Accepted: 05/31/2021] [Indexed: 11/11/2022] Open
Abstract
Reactive oxygen species (ROS) derived from NADPH oxidases (NOX) plays an essential role in advanced glycation end products (AGEs)-induced diabetic vascular endothelial dysfunction. Peroxidasin (PXDN, VPO1) is one member of peroxidases family that catalyzes hydrogen peroxide (H2O2) to hypochlorous acid (HOCl). This present study aimed to elucidate the role of PXDN in promoting vascular endothelial dysfunction induced by AGEs in diabetes mellitus. We found that, compared to non-diabetic (db/m) mice, PXDN expression was notably increased in db/db mice with impaired endothelium-dependent relaxation. Knockdown of PXDN in vivo through tail vein injection of siRNA restored the impaired endothelium-dependent relaxation function of db/db mice which is accompanied with up-regulation of eNOS Ser1177 phosphorylation and NO production. AGEs significantly elevated expression of PXDN and 3-Cl-Tyr, but decreased phosphorylation of Akt and eNOS and NO release in HUVECs. All these effects induced by AGEs were remarkable alleviated by silencing PXDN with small interfering RNAs. In addition, HOCl treatment alone as well as HOCl added with Akt inhibitor MK2206 inhibited phosphorylation of Akt and eNOS, reducing NO production. More importantly,AGEs-induced up-regulation of PXDN and 3-Cl-Tyr with endothelial dysfunction were transformed by NOX2 silencing and H2O2 scavengers. Thus, these results support the conclusion that PXDN promotes AGEs-induced diabetic vascular endothelial dysfunction by attenuating eNOS phosphorylation at Ser1177 via NOX2/HOCl/Akt pathway.
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Affiliation(s)
- Jing Cao
- Department of Cardiovascular Medicine, The Third Xiangya Hospital of Central South University, 410013, Changsha, China.
| | - Guogang Zhang
- Department of Cardiovascular Medicine, The Third Xiangya Hospital of Central South University, 410013, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Zhaoya Liu
- Department of Geriatrics, The Third Xiangya Hospital of Central South University, 410013, Changsha, China.
| | - Qian Xu
- Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University, 410008, Changsha, China.
| | - Chan Li
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, 41008, Changsha, China.
| | - Guangjie Cheng
- Division of Pulmonary, Allergy & Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, 35294, AL, USA.
| | - Ruizheng Shi
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, 41008, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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9
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Wang D, Sant S, Ferrell N. A Biomimetic In Vitro Model of the Kidney Filtration Barrier Using Tissue-Derived Glomerular Basement Membrane. Adv Healthc Mater 2021; 10:e2002275. [PMID: 34218528 DOI: 10.1002/adhm.202002275] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 05/24/2021] [Indexed: 01/28/2023]
Abstract
The glomerular filtration barrier (GFB) filters the blood to remove toxins while retaining high molecular weight proteins in the circulation. The glomerular basement membrane (GBM) and podocytes, highly specialized epithelial cells, are critical components of the filtration barrier. The GBM serves as a physical barrier to passage of molecules into the filtrate. Podocytes adhere to the filtrate side of the GBM and further restrict passage of high molecular weight molecules into the filtrate. Here, a 3D cell culture model of the glomerular filtration barrier to evaluate the role of the GBM and podocytes in mediating molecular diffusion is developed. GBM is isolated from mammalian kidneys to recapitulate the composition and mechanics of the in vivo basement membrane. The GFB model exhibits molecular selectivity that is comparable to the in vivo filtration barrier. The GBM alone provides a stringent barrier to passage of albumin and Ficoll. Podocytes further restrict molecular diffusion. Damage to the GBM that is typical of diabetic kidney disease is simulated using hypochlorous acid and results in increased molecular diffusion. This system can serve as a platform to evaluate the effects of GBM damage, podocyte injury, and reciprocal effects of altered podocyte-GBM interactions on kidney microvascular permeability.
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Affiliation(s)
- Dan Wang
- Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, 1161 21st Ave. South, Nashville, TN, 37232, USA
| | - Snehal Sant
- Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, 1161 21st Ave. South, Nashville, TN, 37232, USA
| | - Nicholas Ferrell
- Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, 1161 21st Ave. South, Nashville, TN, 37232, USA
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37235, USA
- Vanderbilt Center for Kidney Disease, S3223 Medical Center North, Nashville, TN, 37232, USA
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10
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Das UN. Molecular biochemical aspects of salt (sodium chloride) in inflammation and immune response with reference to hypertension and type 2 diabetes mellitus. Lipids Health Dis 2021; 20:83. [PMID: 34334139 PMCID: PMC8327432 DOI: 10.1186/s12944-021-01507-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 07/14/2021] [Indexed: 12/18/2022] Open
Abstract
Obesity, insulin resistance, type 2 diabetes mellitus (T2DM) and hypertension (HTN) are common that are associated with low-grade systemic inflammation. Diet, genetic factors, inflammation, and immunocytes and their cytokines play a role in their pathobiology. But the exact role of sodium, potassium, magnesium and other minerals, trace elements and vitamins in the pathogenesis of HTN and T2DM is not known. Recent studies showed that sodium and potassium can modulate oxidative stress, inflammation, alter the autonomic nervous system and induce dysfunction of the innate and adaptive immune responses in addition to their action on renin-angiotensin-aldosterone system. These actions of sodium, potassium and magnesium and other minerals, trace elements and vitamins are likely to be secondary to their action on pro-inflammatory cytokines IL-6, TNF-α and IL-17 and metabolism of essential fatty acids that may account for their involvement in the pathobiology of insulin resistance, T2DM, HTN and autoimmune diseases.
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Affiliation(s)
- Undurti N Das
- UND Life Sciences, 2221 NW 5th St, Battle Ground, WA, 98604, USA.
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Viurcos-Sanabria R, Escobedo G. Immunometabolic bases of type 2 diabetes in the severity of COVID-19. World J Diabetes 2021; 12:1026-1041. [PMID: 34326952 PMCID: PMC8311488 DOI: 10.4239/wjd.v12.i7.1026] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/16/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 and type 2 diabetes (T2D) have now merged into an ongoing global syndemic that is threatening the lives of millions of people around the globe. For this reason, there is a deep need to understand the immunometabolic bases of the main etiological factors of T2D that affect the severity of COVID-19. Here, we discuss how hyperglycemia contributes to the cytokine storm commonly associated with COVID-19 by stimulating monocytes and macrophages to produce interleukin IL-1β, IL-6, and TNF-α in the airway epithelium. The main mechanisms through which hyperglycemia promotes reactive oxygen species release, inhibition of T cell activation, and neutrophil extracellular traps in the lungs of patients with severe SARS-CoV-2 infection are also studied. We further examine the molecular mechanisms by which proinflammatory cytokines induce insulin resistance, and their deleterious effects on pancreatic β-cell exhaustion in T2D patients critically ill with COVID-19. We address the effect of excess glucose on advanced glycation end product (AGE) formation and the role of AGEs in perpetuating pneumonia and acute respiratory distress syndrome. Finally, we discuss the contribution of preexisting endothelial dysfunction secondary to diabetes in the development of neutrophil trafficking, vascular leaking, and thrombotic events in patients with severe SARS-CoV-2 infection. As we outline here, T2D acts in synergy with SARS-CoV-2 infection to increase the progression, severity, and mortality of COVID-19. We think a better understanding of the T2D-related immunometabolic factors that contribute to exacerbate the severity of COVID-19 will improve our ability to identify patients with high mortality risk and prevent adverse outcomes.
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Affiliation(s)
| | - Galileo Escobedo
- Laboratorio de Proteómica, Dirección de Investigación, Hospital General de Mexico “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico
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12
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Mohammad JA, Fathi ZH, Allwash TA. Assessment the effects of insulin on adiponectin, nitric oxide, myeloperoxidase and lipid profile in type 1 diabetic patients. PHARMACIA 2021. [DOI: 10.3897/pharmacia.68.e63449] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Type 1 diabetes (T1DM) is well recognized risk factor cardiovascular disease (CVD). Insulin therapy is recommended for all patients with type 1 diabetes. Previous findings showed that diabetes impairs endothelial function and increased glucose level reduces nitric oxide (NO) output and increases myeloperoxidase (MPO) activity. However, adiponectin (APN) decreases serum glucose levels. The current study evaluated effects of insulin therapy on circulating levels of oxidative stress and CVD biomarkers like NO, APN, MPO, AIP and lipid profile in type 1 diabetic patients. Fifty patients with T1DM and 18 healthy people were enrolled in this study. The recruited people with T1DM were classified into two groups: 22 newly diagnosed (untreated) type 1 diabetic patients and 28 insulin treated patients. In all groups, circulating NO, APN, MPO, AIP and lipids levels were measured. Compared to control, untreated diabetes revealed a significant increase in the serum levels of APN, MPO, TG, VLDL, TC, LDL and AIP, with a marked reduction in NO and HDL levels. However, insulin therapy significantly lowered MPO, TC and LDL, with no significant changes in the other biochemical parameters. As expected, oxidative stress and CVD-associated markers were significantly increased in untreated diabetes. Insulin therapy exhibited a relatively positive effect on oxidative stress and CVD biomarkers. Accordingly, insulin plus antioxidant supplementation required to normalize these parameters.
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13
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Myeloperoxidase: Mechanisms, reactions and inhibition as a therapeutic strategy in inflammatory diseases. Pharmacol Ther 2021; 218:107685. [DOI: 10.1016/j.pharmthera.2020.107685] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 09/09/2020] [Indexed: 12/17/2022]
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14
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Tian R, Jin Z, Zhou L, Zeng XP, Lu N. Quercetin Attenuated Myeloperoxidase-Dependent HOCl Generation and Endothelial Dysfunction in Diabetic Vasculature. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:404-413. [PMID: 33395297 DOI: 10.1021/acs.jafc.0c06335] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Myeloperoxidase (MPO)-dependent hypochlorous acid (HOCl) generation plays crucial roles in diabetic vascular complications. As a natural polyphenol, quercetin has antioxidant properties in various diabetic models. Herein, we investigated the therapeutic mechanism for quercetin on MPO-mediated HOCl generation and endothelial dysfunction in diabetic vasculature. In vitro, the presence of MPO could amplify high glucose-induced endothelial dysfunction which was significantly inhibited by the NADPH oxidase inhibitor, HOCl or H2O2 scavengers, revealing the contribution of MPO/H2O2/HOCl to vascular endothelial injury. Furthermore, quercetin effectively inhibited MPO/high glucose-mediated HOCl generation and cytotoxicity to vascular endothelial cells. The inhibitive effect on MPO activity was related to the fact that quercetin reduced high glucose-induced H2O2 generation in endothelial cells and directly acted as a competitive substrate for MPO, thus limiting MPO/H2O2-dependent HOCl production. Moreover, quercetin could attenuate HOCl-caused endothelial dysfunction in endothelial cells and isolated aortas. In vivo, dietary quercetin significantly inhibited aortic endothelial dysfunction in diabetic mice, while this compound simultaneously suppressed vascular MPO expression and activity. Therefore, it was demonstrated herein that quercetin inhibited endothelial injury in diabetic vasculature via suppression of MPO/high glucose-dependent HOCl formation.
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Affiliation(s)
- Rong Tian
- MOE Key Laboratory of Functional Small Organic Molecule, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Zeran Jin
- MOE Key Laboratory of Functional Small Organic Molecule, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Lan Zhou
- MOE Key Laboratory of Functional Small Organic Molecule, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Xing-Ping Zeng
- MOE Key Laboratory of Functional Small Organic Molecule, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
| | - Naihao Lu
- MOE Key Laboratory of Functional Small Organic Molecule, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
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15
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Myeloperoxidase: A versatile mediator of endothelial dysfunction and therapeutic target during cardiovascular disease. Pharmacol Ther 2020; 221:107711. [PMID: 33137376 DOI: 10.1016/j.pharmthera.2020.107711] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 10/01/2020] [Indexed: 02/06/2023]
Abstract
Myeloperoxidase (MPO) is a prominent mammalian heme peroxidase and a fundamental component of the innate immune response against microbial pathogens. In recent times, MPO has received considerable attention as a key oxidative enzyme capable of impairing the bioactivity of nitric oxide (NO) and promoting endothelial dysfunction; a clinically relevant event that manifests throughout the development of inflammatory cardiovascular disease. Increasing evidence indicates that during cardiovascular disease, MPO is released intravascularly by activated leukocytes resulting in its transport and sequestration within the vascular endothelium. At this site, MPO catalyzes various oxidative reactions that are capable of promoting vascular inflammation and impairing NO bioactivity and endothelial function. In particular, MPO catalyzes the production of the potent oxidant hypochlorous acid (HOCl) and the catalytic consumption of NO via the enzyme's NO oxidase activity. An emerging paradigm is the ability of MPO to also influence endothelial function via non-catalytic, cytokine-like activities. In this review article we discuss the implications of our increasing knowledge of the versatility of MPO's actions as a mediator of cardiovascular disease and endothelial dysfunction for the development of new pharmacological agents capable of effectively combating MPO's pathogenic activities. More specifically, we will (i) discuss the various transport mechanisms by which MPO accumulates into the endothelium of inflamed or diseased arteries, (ii) detail the clinical and basic scientific evidence identifying MPO as a significant cause of endothelial dysfunction and cardiovascular disease, (iii) provide an up-to-date coverage on the different oxidative mechanisms by which MPO can impair endothelial function during cardiovascular disease including an evaluation of the contributions of MPO-catalyzed HOCl production and NO oxidation, and (iv) outline the novel non-enzymatic mechanisms of MPO and their potential contribution to endothelial dysfunction. Finally, we deliver a detailed appraisal of the different pharmacological strategies available for targeting the catalytic and non-catalytic modes-of-action of MPO in order to protect against endothelial dysfunction in cardiovascular disease.
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16
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Alexandrovski M, Suciu S, Alexandrovski J. Joint Measurements of Leukocyte Elastase and Myeloperoxidase Promote Identification of the State of Neutrophils in Diabetic Patients. Biores Open Access 2020; 9:190-197. [PMID: 32908806 PMCID: PMC7473041 DOI: 10.1089/biores.2020.0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2020] [Indexed: 11/18/2022] Open
Abstract
The clinic of diabetes mellitus (DM) offers a number of hypotheses about the leading role of polymorphonuclear neutrophils (PMNs) in both oxidative stress and diabetic complications. However, the results of numerous studies are extremely controversial. Why is it so? We appreciated the clinical significance of simultaneous measurement data of several PMN parameters, which must complement each other. For this purpose, myeloperoxidase (MPO) and elastase (EL) were jointly analyzed in the blood plasma from 160 type 2 diabetes mellitus patients with high levels of HbA1c. A weakly positive correlation (r ∼ 0.56) was observed between MPO and EL analytical data, and any correlation between the concentrations of MPO/EL and HbA1c was absent. Medians of 160 measurements of MPO/EL concentrations were ∼103/190 ng/mL, and 95% of all results were in the range below 320/1016 ng/mL, respectively. The share of DM patients whose concentrations of MPO, EL, or either of two parameters exceeded the corresponding reference values was 65%, 80%, and 82.5%, respectively. These findings—a high intensity of neutrophil degranulation process—indicated that some diabetic conditions promote the transfer of PMNs to an “arousal” or “subactivation” state, which is identical or similar to their activation, providing in vivo an almost inexhaustible source of extremely “aggressive” MPO and EL. Thus, the conjoint MPO/EL measurements confirm the leading role of PMNs in the development of various complications of diabetes. The paradox is that the diagnostic significance of MPO/EL as independent parameters in diabetic patients is unambiguous for a number of reasons.
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Affiliation(s)
| | - Soimita Suciu
- Department of Physiology, Cluj-Napoca University of Medicine and Pharmacy, Cluj, Romania
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17
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Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System. Front Immunol 2020; 11:1582. [PMID: 32793223 PMCID: PMC7387426 DOI: 10.3389/fimmu.2020.01582] [Citation(s) in RCA: 285] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 06/15/2020] [Indexed: 12/14/2022] Open
Abstract
Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases.
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Affiliation(s)
- Gholamreza Daryabor
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohamad Reza Atashzar
- Department of Immunology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | | | - Seppo Meri
- Department of Bacteriology and Immunology and the Translational Immunology Research Program (TRIMM), The University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Kurosh Kalantar
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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18
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Orion D, von Landenberg P, Itsekson-Hayosh Z, Schwammenthal Y, Tsabari R, Merzeliak O, Chapman J, Tanne D. Plasma myeloperoxidase levels in acute brain ischaemia and high grade carotid stenosis. Eur J Neurol 2020; 27:1604-1611. [PMID: 32335972 DOI: 10.1111/ene.14279] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 04/15/2020] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND PURPOSE Myeloperoxidase (MPO) is an important oxidative enzyme participating in different stages of cardiovascular disease and predicts prognosis. Little is known about its role in acute cerebrovascular events and carotid plaque vulnerability. In this study, the aim was to assess plasma MPO levels in acute stroke patients and their correlation to stroke severity and stroke outcome. METHODS Plasma MPO levels were assessed in patients presenting with acute brain ischaemia within 36 h of symptom onset (n = 144, mean age 64.7 ± 11.6 years, 67% men) and in patients with moderate-to-severe carotid stenosis undergoing carotid artery stenting (n = 51, mean age 66.3 ± 8.4 years, 75% men). Patients presenting with acute brain ischaemia were assessed serially for stroke severity and disability. RESULTS Plasma MPO concentrations (ng/ml) were associated with interleukin-6 (r = 0.38, P < 0.0001) and gender (median interquartile range) of 68.6 (49.8-107.0) vs. 59.7 (42.7-85.5) in women vs. men (P = 0.02). In acute brain ischaemia, MPO concentrations were associated with non-lacunar subtype (bottom, middle and top tertiles 37.5%, 71.7% and 71.7% respectively; P = 0.001), with stroke severity (baseline National Institutes of Health Stroke Scale score > 10, bottom, middle and top tertiles 6.3%, vs. 41.7% and 31.3%, respectively; P < 0.006) as well as with stroke severity at days 1-2, days 4-5 and at discharge (P < 0.05 for all), but less with disability at discharge (modified Rankin Scale score ≥ 2, 41.7% vs. 60.4% and 58.7% for the bottom, middle and top tertiles, respectively; P = 0.096). CONCLUSIONS Amongst patients with acute brain ischaemia, plasma MPO concentrations were associated with stroke severity and non-lacunar subtype, but not with long-term functional disability.
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Affiliation(s)
- D Orion
- Department of Neurology and Sagol Neuroscience Center, Stroke Center, Sheba Medical Center, Tel Hashomer, Israel
| | - P von Landenberg
- Institute of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg Universität Mainz Klinikum, Mainz, Germany
| | - Z Itsekson-Hayosh
- Department of Neurology and Sagol Neuroscience Center, Stroke Center, Sheba Medical Center, Tel Hashomer, Israel
| | - Y Schwammenthal
- Department of Neurology and Sagol Neuroscience Center, Stroke Center, Sheba Medical Center, Tel Hashomer, Israel
| | - R Tsabari
- Department of Neurology and Sagol Neuroscience Center, Stroke Center, Sheba Medical Center, Tel Hashomer, Israel
| | - O Merzeliak
- Department of Neurology and Sagol Neuroscience Center, Stroke Center, Sheba Medical Center, Tel Hashomer, Israel
| | - J Chapman
- Department of Neurology and Sagol Neuroscience Center, Stroke Center, Sheba Medical Center, Tel Hashomer, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - D Tanne
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Stroke and Cognition Institute, Rambam Health Care Campus, Haifa, Israel
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19
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Davies MJ, Hawkins CL. The Role of Myeloperoxidase in Biomolecule Modification, Chronic Inflammation, and Disease. Antioxid Redox Signal 2020; 32:957-981. [PMID: 31989833 DOI: 10.1089/ars.2020.8030] [Citation(s) in RCA: 192] [Impact Index Per Article: 38.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Significance: The release of myeloperoxidase (MPO) by activated leukocytes is critical in innate immune responses. MPO produces hypochlorous acid (HOCl) and other strong oxidants, which kill bacteria and other invading pathogens. However, MPO also drives the development of numerous chronic inflammatory pathologies, including atherosclerosis, neurodegenerative disease, lung disease, arthritis, cancer, and kidney disease, which are globally responsible for significant patient mortality and morbidity. Recent Advances: The development of imaging approaches to precisely identify the localization of MPO and the molecular targets of HOCl in vivo is an important advance, as typically the involvement of MPO in inflammatory disease has been inferred by its presence, together with the detection of biomarkers of HOCl, in biological fluids or diseased tissues. This will provide valuable information in regard to the cell types responsible for releasing MPO in vivo, together with new insight into potential therapeutic opportunities. Critical Issues: Although there is little doubt as to the value of MPO inhibition as a protective strategy to mitigate tissue damage during chronic inflammation in experimental models, the impact of long-term inhibition of MPO as a therapeutic strategy for human disease remains uncertain, in light of the potential effects on innate immunity. Future Directions: The development of more targeted MPO inhibitors or a treatment regimen designed to reduce MPO-associated host tissue damage without compromising pathogen killing by the innate immune system is therefore an important future direction. Similarly, a partial MPO inhibition strategy may be sufficient to maintain adequate bacterial activity while decreasing the propagation of inflammatory pathologies.
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Affiliation(s)
- Michael J Davies
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen N, Denmark
| | - Clare L Hawkins
- Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen N, Denmark
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20
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Qaddoumi MG, Alanbaei M, Hammad MM, Al Khairi I, Cherian P, Channanath A, Thanaraj TA, Al-Mulla F, Abu-Farha M, Abubaker J. Investigating the Role of Myeloperoxidase and Angiopoietin-like Protein 6 in Obesity and Diabetes. Sci Rep 2020; 10:6170. [PMID: 32277104 PMCID: PMC7148302 DOI: 10.1038/s41598-020-63149-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 03/02/2020] [Indexed: 02/07/2023] Open
Abstract
Myeloperoxidase (MPO) is positively associated with obesity and diet-induced insulin resistance. Angiopoietin-like protein 6 (ANGPTL6) regulates metabolic processes and counteract obesity through increased energy expenditure. This study aims to evaluate the plasma MPO and ANGPTL6 levels in obese and diabetic individuals as well as MPO association with biochemical markers of obesity. A total of 238 participants were enrolled, including 137 control and 101 type 2 diabetes (T2D) patients. ANGPTL6 and MPO levels and other biomarkers were measured via ELISA. ANGPTL6 levels were significantly higher in the diabetic population and obese individuals. When the group was stratified based on T2D, ANGPTL6 levels were significantly higher in obese-diabetic participants compared with non-obese-diabetics, but obese-non-diabetic individuals had similar ANGPTL6 levels to their controls. MPO levels were higher in obese compared with non-obese participants but did not differ between T2D and control participants. MPO levels were upregulated in obese compared with non-obese in both diabetics and non-diabetics. MPO was positively associated with ANGPTL6, triglyceride, BMI, TNF-alpha, high-sensitivity C-reactive protein, interleukin-6, and plasminogen activator inhibitor-1. Taken together, our findings suggest that both MPO and ANGPTL6 may regulate obesity, although MPO exerts this effect independent of diabetes while ANGPTL6 may have a modulatory role in diabetes.
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Affiliation(s)
- Mohammad G Qaddoumi
- Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
- Pharmacology and Therapeutics Department, Faculty of Pharmacy, Kuwait University, Kuwait City, Kuwait
| | - Muath Alanbaei
- Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Maha M Hammad
- Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Irina Al Khairi
- Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Preethi Cherian
- Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Arshad Channanath
- Functional Genomic Unit, Dasman Diabetes Institute, 15462, Kuwait City, Kuwait
| | | | - Fahd Al-Mulla
- Functional Genomic Unit, Dasman Diabetes Institute, 15462, Kuwait City, Kuwait
| | - Mohamed Abu-Farha
- Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait.
| | - Jehad Abubaker
- Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait City, Kuwait.
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21
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Chai W, Aylor K, Liu Z, Gan LM, Michaëlsson E, Barrett E. Inhibiting myeloperoxidase prevents onset and reverses established high-fat diet-induced microvascular insulin resistance. Am J Physiol Endocrinol Metab 2019; 317:E1063-E1069. [PMID: 31593502 DOI: 10.1152/ajpendo.00203.2019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A high-fat diet (HFD) can rapidly recruit neutrophils to insulin target tissues and within days induce microvascular insulin resistance (IR). Myeloperoxidase (MPO) is highly enriched in neutrophils, can inhibit nitric oxide-mediated vasorelaxation in vitro and is associated with increased cardiovascular disease risk. AZD5904 irreversibly inhibits MPO and in human clinical trials. MPO knockout, or chemical inhibition, blunts HFD-induced metabolic IR in mice. Whether MPO affects microvascular IR or muscle metabolic insulin sensitivity in vivo is unknown. We used contrast-enhanced ultrasound and the euglycemic insulin clamp to test whether inhibiting MPO could prevent the development or reverse established HFD-induced metabolic and/or microvascular IR in Sprague-Dawley rats. Two weeks of HFD feeding blocked insulin-mediated skeletal muscle capillary recruitment, inhibited glucose utilization, and insulin signaling to muscle. Continuous subcutaneous AZD5904 infusion during the 2 wk selectively blocked HFD's microvascular effect. Furthermore, AZD5904 infusion during the last 2 of 4 wk of HFD feeding restored microvascular insulin sensitivity but not metabolic IR. We conclude that inhibiting MPO selectively improves vascular IR. This selective microvascular effect may connote a therapeutic potential for MPO inhibition in the prevention of vascular disease/dysfunction seen in IR humans.
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Affiliation(s)
- Weidong Chai
- Division of Endocrinology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Kevin Aylor
- Division of Endocrinology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Zhenqi Liu
- Division of Endocrinology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Li-Ming Gan
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - Erik Michaëlsson
- Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - Eugene Barrett
- Division of Endocrinology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia
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22
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Zhang J, Bao Y, Zhou X, Zheng L. Polycystic ovary syndrome and mitochondrial dysfunction. Reprod Biol Endocrinol 2019; 17:67. [PMID: 31420039 PMCID: PMC6698037 DOI: 10.1186/s12958-019-0509-4] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 08/01/2019] [Indexed: 02/07/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is a prevalent hormonal disorder of premenopausal women worldwide and is characterized by reproductive, endocrine, and metabolic abnormalities. The clinical manifestations of PCOS include oligomenorrhea or amenorrhea, hyperandrogenism, ovarian polycystic changes, and infertility. Women with PCOS are at an increased risk of suffering from type 2 diabetes; me\tabolic syndrome; cardiovascular events, such as hypertension, dyslipidemia; gynecological diseases, including infertility, endometrial dysplasia, endometrial cancer, and ovarian malignant tumors; pregnancy complications, such as premature birth, low birthweight, and eclampsia; and emotional and mental disorders in the future. Although numerous studies have focused on PCOS, the underlying pathophysiological mechanisms of this disease remain unclear. Mitochondria play a key role in energy production, and mitochondrial dysfunction at the cellular level can affect systemic metabolic balance. The recent wide acceptance of functional mitochondrial disorders as a correlated factor of numerous diseases has led to the presupposition that abnormal mitochondrial metabolic markers are associated with PCOS. Studies conducted in the past few years have confirmed that increased oxidative stress is associated with the progression and related complications of PCOS and have proven the relationship between other mitochondrial dysfunctions and PCOS. Thus, this review aims to summarize and discuss previous and recent findings concerning the relationship between mitochondrial dysfunction and PCOS.
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Affiliation(s)
- Jingshun Zhang
- grid.452829.0Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin China
| | - Yigang Bao
- grid.452829.0Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin China
| | - Xu Zhou
- 0000 0004 1760 5735grid.64924.3dCollege of Animal Sciences, Jilin University, Changchun, Jilin China
| | - Lianwen Zheng
- grid.452829.0Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin China
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A Low Glycemic Index Decreases Inflammation by Increasing the Concentration of Uric Acid and the Activity of Glutathione Peroxidase (GPx3) in Patients with Polycystic Ovary Syndrome (PCOS). Molecules 2019; 24:molecules24081508. [PMID: 30999628 PMCID: PMC6514917 DOI: 10.3390/molecules24081508] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 04/14/2019] [Accepted: 04/16/2019] [Indexed: 11/17/2022] Open
Abstract
Introduction: According to a review of the literature, there is a lack of data on the mechanisms that participate in the suppression of inflammation that accompanies polycystic ovary syndrome (PCOS). Additionally, the changes in oxidative status resulting from a low-calorie diet have not been studied in a group of women with PCOS, and the oxidation and reduction processes associated with PCOS have not been explained. Material and methods: The study involved 49 women who were diagnosed with PCOS according to Rotterdam’s criteria, and 24 women voluntarily agreed to a three-month dietary intervention. The dietary intervention was carried out for 3 months. Glutathione peroxidase (GPx3) activity, the Ferric reducing ability of plasma, and uric acid concentration were measured spectrophotometrically both before and after the intervention. Statistical analysis was performed with the Statistica 10.0 software package, and a Pearson’s correlation matrix was generated. Results: A lower concentration of GPx3 was observed in women with PCOS (before the dietetic intervention began) compared with the GPx3 levels in healthy women. A relationship was shown between GPx3 levels and the concentration of prolactin, insulin on fasting, and triglycerides. After the dietary intervention, increases in uric acid and GPx3 activity were noted, as well as numerous relationships between anthropometric and biochemical parameters. The ferric reducing/antioxidant power did not change significantly. Conclusions: Inhibiting the effect of prolactin (by the level of reactive oxygen species) on the activity of GPx3 could be a starting point for the increase in antioxidative stress and the development of the inflammatory state associated with PCOS pathophysiology. Following a low-calorie diet with a lower glycemic index is proposed to silence inflammation by increasing the concentration of uric acid. During GPx3 mobilization, women with PCOS have a higher demand for selenium, and its deficiencies may contribute to disordered thyroid hormone synthesis. The three-month dietary intervention did not silence redox processes in the examined group of women.
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Brown KL, Hudson BG, Voziyan PA. Halogens are key cofactors in building of collagen IV scaffolds outside the cell. Curr Opin Nephrol Hypertens 2019; 27:171-175. [PMID: 29547404 DOI: 10.1097/mnh.0000000000000401] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review is to highlight recent advances in understanding the molecular assembly of basement membranes, as exemplified by the glomerular basement membrane (GBM) of the kidney filtration apparatus. In particular, an essential role of halogens in the basement membrane formation has been discovered. RECENT FINDINGS Extracellular chloride triggers a molecular switch within non collagenous domains of collagen IV that induces protomer oligomerization and scaffold assembly outside the cell. Moreover, bromide is an essential cofactor in enzymatic cross-linking that reinforces the stability of scaffolds. Halogenation and halogen-induced oxidation of the collagen IV scaffold in disease states damage scaffold function. SUMMARY Halogens play an essential role in the formation of collagen IV scaffolds of basement membranes. Pathogenic damage of these scaffolds by halogenation and halogen-induced oxidation is a potential target for therapeutic interventions.
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Affiliation(s)
- Kyle L Brown
- Department of Medicine, Division of Nephrology.,Center for Structural Biology.,Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Billy G Hudson
- Department of Medicine, Division of Nephrology.,Department of Biochemistry.,Department of Cell and Developmental Biology.,Department of Pathology, Microbiology and Immunology.,Center for Structural Biology.,Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Paul A Voziyan
- Department of Medicine, Division of Nephrology.,Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Etwebi Z, Landesberg G, Preston K, Eguchi S, Scalia R. Mechanistic Role of the Calcium-Dependent Protease Calpain in the Endothelial Dysfunction Induced by MPO (Myeloperoxidase). Hypertension 2019; 71:761-770. [PMID: 29507101 DOI: 10.1161/hypertensionaha.117.10305] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Revised: 10/02/2017] [Accepted: 01/12/2018] [Indexed: 01/07/2023]
Abstract
MPO (myeloperoxidase) is a peroxidase enzyme secreted by activated leukocytes that plays a pathogenic role in cardiovascular disease, mainly by initiating endothelial dysfunction. The molecular mechanisms of the endothelial damaging action of MPO remain though largely elusive. Calpain is a calcium-dependent protease expressed in the vascular wall. Activation of calpains has been implicated in inflammatory disorders of the vasculature. Using endothelial cells and genetically modified mice, this study identifies the µ-calpain isoform as novel downstream signaling target of MPO in endothelial dysfunction. Mouse lung microvascular endothelial cells were stimulated with 10 nmol/L MPO for 180 minutes. MPO denitrosylated µ-calpain C-terminus domain, and time dependently activated µ-calpain, but not the m-calpain isoform. MPO also reduced Thr172 AMPK (AMP-activated protein kinase) and Ser1177 eNOS (endothelial nitric oxide synthase) phosphorylation via upregulation of PP2A (protein phosphatase 2) expression. At the functional level, MPO increased endothelial VCAM-1 (vascular cell adhesion molecule 1) abundance and the adhesion of leukocytes to the mouse aorta. In MPO-treated endothelial cells, pharmacological inhibition of calpain activity attenuated expression of VCAM-1 and PP2A, and restored Thr172 AMPK and Ser1177 eNOS phosphorylation. Compared with wild-type mice, µ-calpain deficient mice experienced reduced leukocyte adhesion to the aortic endothelium in response to MPO. Our data first establish a role for calpain in the endothelial dysfunction and vascular inflammation of MPO. The MPO/calpain/PP2A signaling pathway may provide novel pharmacological targets for the treatment of inflammatory vascular disorders.
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Affiliation(s)
- Zienab Etwebi
- From the Department of Physiology and the Cardiovascular Research Center, Temple University, Philadelphia, PA
| | - Gavin Landesberg
- From the Department of Physiology and the Cardiovascular Research Center, Temple University, Philadelphia, PA
| | - Kyle Preston
- From the Department of Physiology and the Cardiovascular Research Center, Temple University, Philadelphia, PA
| | - Satoru Eguchi
- From the Department of Physiology and the Cardiovascular Research Center, Temple University, Philadelphia, PA
| | - Rosario Scalia
- From the Department of Physiology and the Cardiovascular Research Center, Temple University, Philadelphia, PA.
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26
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Oxidation of cysteine by ceruloplasmin leads to formation of hydrogen peroxide, which can be utilized by myeloperoxidase. Biochem Biophys Res Commun 2018; 503:2146-2151. [DOI: 10.1016/j.bbrc.2018.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 08/01/2018] [Indexed: 01/08/2023]
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27
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Tian R, Ding Y, Peng YY, Lu N. Myeloperoxidase amplified high glucose-induced endothelial dysfunction in vasculature: Role of NADPH oxidase and hypochlorous acid. Biochem Biophys Res Commun 2017; 484:572-578. [PMID: 28131839 DOI: 10.1016/j.bbrc.2017.01.132] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 01/24/2017] [Indexed: 12/11/2022]
Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS) such as superoxide and hydrogen peroxide (H2O2), have emerged as important molecules in the pathogenesis of diabetic endothelial dysfunction. Additionally, neutrophils-derived myeloperoxidase (MPO) and MPO-catalyzed hypochlorous acid (HOCl) play important roles in the vascular injury. However, it is unknown whether MPO can use vascular-derived ROS to induce diabetic endothelial dysfunction. In the present study, we demonstrated that NADPH oxidase was the main source of ROS formation in high glucose-cultured human umbilical vein endothelial cells (HUVECs), and played a critical role in high glucose-induced endothelial dysfunction such as cell apoptosis, loss of cell viability and reduction of nitric oxide (NO). However, the addition of MPO could amplify the high glucose-induced endothelial dysfunction which was inhibited by the presence of apocynin (NADPH oxidase inhibitor), catalase (H2O2 scavenger), or methionine (HOCl scavenger), demonstrating the contribution of NADPH oxidase-H2O2-MPO-HOCl pathway in the MPO/high glucose-induced vascular injury. In high glucose-incubated rat aortas, MPO also exacerbated the NADPH oxidase-induced impairment of endothelium-dependent relaxation. Consistent with these in vitro data, in diabetic rat aortas, both MPO expresion and NADPH oxidase activity were increased while the endothelial function was simultaneously impaired. The results suggested that vascular-bound MPO could amplify high glucose-induced vascular injury in diabetes. MPO-NADPH oxidase-HOCl may represent an important pathogenic pathway in diabetic vascular diseases.
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Affiliation(s)
- Rong Tian
- Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China
| | - Yun Ding
- Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China
| | - Yi-Yuan Peng
- Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China
| | - Naihao Lu
- Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China.
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Côté-Gravel J, Brouillette E, Obradović N, Ster C, Talbot BG, Malouin F. Characterization of a vraG Mutant in a Genetically Stable Staphylococcus aureus Small-Colony Variant and Preliminary Assessment for Use as a Live-Attenuated Vaccine against Intrammamary Infections. PLoS One 2016; 11:e0166621. [PMID: 27855187 PMCID: PMC5113970 DOI: 10.1371/journal.pone.0166621] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 11/01/2016] [Indexed: 12/14/2022] Open
Abstract
Staphylococcus aureus is a leading cause of bovine intramammary infections (IMIs) that can evolve into difficult-to-treat chronic mastitis. To date, no vaccine formulation has shown high protective efficacy against S. aureus IMI, partly because this bacterium can efficiently evade the immune system. For instance, S. aureus small colony variants (SCVs) have intracellular abilities and can persist without producing invasive infections. As a first step towards the development of a live vaccine, this study describes the elaboration of a novel attenuated mutant of S. aureus taking advantage of the SCV phenotype. A genetically stable SCV was created through the deletion of the hemB gene, impairing its ability to adapt and revert to the invasive phenotype. Further attenuation was obtained through inactivation of gene vraG (SACOL0720) which we previously showed to be important for full virulence during bovine IMIs. After infection of bovine mammary epithelial cells (MAC-T), the double mutant (ΔvraGΔhemB) was less internalized and caused less cell destruction than that seen with ΔhemB and ΔvraG, respectively. In a murine IMI model, the ΔvraGΔhemB mutant was strongly attenuated, with a reduction of viable counts of up to 5-log10 CFU/g of mammary gland when compared to the parental strain. A complete clearance of ΔvraGΔhemB from glands was observed whereas mortality rapidly (48h) occurred with the wild-type strain. Immunization of mice using subcutaneous injections of live ΔvraGΔhemB raised a strong immune response as judged by the high total IgG titers measured against bacterial cell extracts and by the high IgG2a/IgG1 ratio observed against the IsdH protein. Also, ΔvraGΔhemB had sufficient common features with bovine mastitis strains so that the antibody response also strongly recognized strains from a variety of mastitis associated spa types. This double mutant could serve as a live-attenuated component in vaccines to improve cell-mediated immune responses against S. aureus IMIs.
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Affiliation(s)
- Julie Côté-Gravel
- Centre d’Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Eric Brouillette
- Centre d’Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Nataša Obradović
- Centre d’Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Céline Ster
- Centre d’Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Brian G. Talbot
- Centre d’Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - François Malouin
- Centre d’Étude et de Valorisation de la Diversité Microbienne (CEVDM), Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
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Peng H, Chen L, Huang X, Yang T, Yu Z, Cheng G, Zhang G, Shi R. Vascular peroxidase 1 up regulation by angiotensin II attenuates nitric oxide production through increasing asymmetrical dimethylarginine in HUVECs. ACTA ACUST UNITED AC 2016; 10:741-751.e3. [DOI: 10.1016/j.jash.2016.06.036] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 06/05/2016] [Accepted: 06/18/2016] [Indexed: 12/17/2022]
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30
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Victor VM, Rovira-Llopis S, Bañuls C, Diaz-Morales N, Martinez de Marañon A, Rios-Navarro C, Alvarez A, Gomez M, Rocha M, Hernández-Mijares A. Insulin Resistance in PCOS Patients Enhances Oxidative Stress and Leukocyte Adhesion: Role of Myeloperoxidase. PLoS One 2016; 11:e0151960. [PMID: 27007571 PMCID: PMC4805297 DOI: 10.1371/journal.pone.0151960] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 03/07/2016] [Indexed: 11/18/2022] Open
Abstract
Cardiovascular diseases and oxidative stress are related to polycystic ovary syndrome (PCOS) and insulin resistance (IR). We have evaluated the relationship between myeloperoxidase (MPO) and leukocyte activation in PCOS patients according to homeostatic model assessment of IR (HOMA-IR), and have explored a possible correlation between these factors and endocrine and inflammatory parameters. This was a prospective controlled study conducted in an academic medical center. The study population consisted of 101 PCOS subjects and 105 control subjects. We divided PCOS subjects into PCOS non-IR (HOMA-IR<2.5) and PCOS IR (HOMA-IR>2.5). Metabolic and anthropometric parameters, total and mitochondrial reactive oxygen species (ROS) production, MPO levels, interactions between human umbilical vein endothelial cells and leukocytes, adhesion molecules (E-selectin, ICAM-1 and VCAM-1) and proinflammatory cytokines (IL-6 and TNF-α) were evaluated. Oxidative stress was observed in PCOS patients, in whom there was an increase in total and mitochondrial ROS production and MPO levels. Enhanced rolling flux and adhesion, and a decrease in polymorphonuclear cell rolling velocity were also detected in PCOS subjects. Increases in IL-6 and TNF-α and adhesion molecules (E-selectin, ICAM-1 and VCAM-1) were also observed, particularly in the PCOS IR group, providing evidence that inflammation and oxidative stress are related in PCOS patients. HOMA-IR was positively correlated with hsCRP (p<0.001, r = 0.304), ROS production (p<0.01, r = 0.593), leukocyte rolling flux (p<0.05, r = 0.446), E-selectin (p<0.01, r = 0.436) and IL-6 (p<0.001, r = 0.443). The results show an increase in the rate of ROS and MPO levels in PCOS patients in general, and particularly in those with IR. Inflammation in PCOS induces leukocyte-endothelium interactions and a simultaneous increase in IL-6, TNF-α, E-selectin, ICAM-1 and VCAM-1. These conditions are aggravated by the presence of IR.
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Affiliation(s)
- Victor M. Victor
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
- Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain
- CIBERehd - Department of Pharmacology and Physiology, University of Valencia, Valencia, Spain
- Department of Physiology, University of Valencia, Valencia, Spain
| | - Susana Rovira-Llopis
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
- Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain
| | - Celia Bañuls
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
- Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain
| | - Noelia Diaz-Morales
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
| | - Arantxa Martinez de Marañon
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
| | - Cesar Rios-Navarro
- CIBERehd - Department of Pharmacology and Physiology, University of Valencia, Valencia, Spain
| | - Angeles Alvarez
- CIBERehd - Department of Pharmacology and Physiology, University of Valencia, Valencia, Spain
- General Foundation of the University of Valencia, Valencia, Spain
| | - Marcelino Gomez
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
| | - Milagros Rocha
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
- Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain
- CIBERehd - Department of Pharmacology and Physiology, University of Valencia, Valencia, Spain
| | - Antonio Hernández-Mijares
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
- Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain
- Department of Medicine, University of Valencia, Valencia, Spain
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Madu H, Avance J, Chetyrkin S, Darris C, Rose KL, Sanchez OA, Hudson B, Voziyan P. Pyridoxamine protects proteins from damage by hypohalous acids in vitro and in vivo. Free Radic Biol Med 2015; 89:83-90. [PMID: 26159508 PMCID: PMC4684779 DOI: 10.1016/j.freeradbiomed.2015.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 06/06/2015] [Accepted: 07/01/2015] [Indexed: 01/10/2023]
Abstract
Diabetes is characterized, in part, by activation of toxic oxidative and glycoxidative pathways that are triggered by persistent hyperglycemia and contribute to diabetic complications. Inhibition of these pathways may benefit diabetic patients by delaying the onset of complications. One such inhibitor, pyridoxamine (PM), had shown promise in clinical trials. However, the mechanism of PM action in vivo is not well understood. We have previously reported that hypohalous acids can cause disruption of the structure and function of renal collagen IV in experimental diabetes (K.L. Brown et al., Diabetes 64:2242-2253, 2015). In the present study, we demonstrate that PM can protect protein functionality from hypochlorous and hypobromous acid-derived damage via a rapid direct reaction with and detoxification of these hypohalous acids. We further demonstrate that PM treatment can ameliorate specific hypohalous acid-derived structural and functional damage to the renal collagen IV network in a diabetic animal model. These findings suggest a new mechanism of PM action in diabetes, namely sequestration of hypohalous acids, which may contribute to known therapeutic effects of PM in human diabetic nephropathy.
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Affiliation(s)
- Hartman Madu
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Josh Avance
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Sergei Chetyrkin
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Carl Darris
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Kristie Lindsey Rose
- Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Otto A Sanchez
- Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Billy Hudson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Paul Voziyan
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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Liu SY, Yuan Q, Li XH, Hu CP, Hu R, Zhang GG, Li D, Li YJ. Role of vascular peroxidase 1 in senescence of endothelial cells in diabetes rats. Int J Cardiol 2015; 197:182-91. [DOI: 10.1016/j.ijcard.2015.06.098] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Revised: 06/06/2015] [Accepted: 06/23/2015] [Indexed: 01/22/2023]
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Brown KL, Darris C, Rose KL, Sanchez OA, Madu H, Avance J, Brooks N, Zhang MZ, Fogo A, Harris R, Hudson BG, Voziyan P. Hypohalous acids contribute to renal extracellular matrix damage in experimental diabetes. Diabetes 2015; 64:2242-53. [PMID: 25605804 PMCID: PMC4439565 DOI: 10.2337/db14-1001] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 01/10/2015] [Indexed: 12/17/2022]
Abstract
In diabetes, toxic oxidative pathways are triggered by persistent hyperglycemia and contribute to diabetes complications. A major proposed pathogenic mechanism is the accumulation of protein modifications that are called advanced glycation end products. However, other nonenzymatic post-translational modifications may also contribute to pathogenic protein damage in diabetes. We demonstrate that hypohalous acid-derived modifications of renal tissues and extracellular matrix (ECM) proteins are significantly elevated in experimental diabetic nephropathy. Moreover, diabetic renal ECM shows diminished binding of α1β1 integrin consistent with the modification of collagen IV by hypochlorous (HOCl) and hypobromous acids. Noncollagenous (NC1) hexamers, key connection modules of collagen IV networks, are modified via oxidation and chlorination of tryptophan and bromination of tyrosine residues. Chlorotryptophan, a relatively minor modification, has not been previously found in proteins. In the NC1 hexamers isolated from diabetic kidneys, levels of HOCl-derived oxidized and chlorinated tryptophan residues W(28) and W(192) are significantly elevated compared with nondiabetic controls. Molecular dynamics simulations predicted a more relaxed NC1 hexamer tertiary structure and diminished assembly competence in diabetes; this was confirmed using limited proteolysis and denaturation/refolding. Our results suggest that hypohalous acid-derived modifications of renal ECM, and specifically collagen IV networks, contribute to functional protein damage in diabetes.
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Affiliation(s)
- Kyle L Brown
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Carl Darris
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | | | - Otto A Sanchez
- Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN
| | - Hartman Madu
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | | | | | - Ming-Zhi Zhang
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Agnes Fogo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Raymond Harris
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Billy G Hudson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Paul Voziyan
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
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Csató V, Pető A, Fülöp GÁ, Rutkai I, Pásztor ET, Fagyas M, Kalász J, Édes I, Tóth A, Papp Z. Myeloperoxidase evokes substantial vasomotor responses in isolated skeletal muscle arterioles of the rat. Acta Physiol (Oxf) 2015; 214:109-23. [PMID: 25760778 PMCID: PMC4654238 DOI: 10.1111/apha.12488] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 01/19/2015] [Accepted: 03/09/2015] [Indexed: 12/20/2022]
Abstract
Aims Myeloperoxidase (MPO) catalyses the formation of a wide variety of oxidants, including hypochlorous acid (HOCl), and contributes to cardiovascular disease progression. We hypothesized that during its action MPO evokes substantial vasomotor responses. Methods Following exposure to MPO (1.92 mU mL−1) in the presence of increasing concentrations of hydrogen peroxide (H2O2), changes in arteriolar diameter of isolated gracilis skeletal muscle arterioles (SMAs) and coronary arterioles (CAs) and in the isometric force in basilar arteries (BAs) of the rat were monitored. Results Myeloperoxidase increased vascular tone to different degrees in CAs, SMAs and BAs. The mechanism of increased vasoconstriction was studied in detail in SMAs. MPO-evoked vasoconstrictions were prevented by the MPO inhibitor 4-aminobenzhydrazide (50 μm), by endothelium removal in the SMAs. Surprisingly, the HOCl scavenger L-methionine (100 μm), the thromboxane A2 (TXA2) antagonist SQ-29548 (1 μm) or the non-specific cyclooxygenase (COX) antagonist indomethacin (1 μm) converted the MPO-evoked vasoconstrictions to pronounced vasodilations in SMAs, not seen in the presence of H2O2. In contrast to noradrenaline-induced vasoconstrictions, the MPO-evoked vasoconstrictions were not accompanied by significant increases in arteriolar [Ca2+] levels in SMAs. Conclusion These data showed that H2O2-derived HOCl to be a potent vasoconstrictor upon MPO application. HOCl activated the COX pathway, causing the synthesis and release of a TXA2-like substance to increase the Ca2+ sensitivity of the contractile apparatus in vascular smooth muscle cells and thereby to augment H2O2-evoked vasoconstrictions. Nevertheless, inhibition of the HOCl–COX–TXA2 pathway unmasked the effects of additional MPO-derived radicals with a marked vasodilatory potential in SMAs.
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Affiliation(s)
- V. Csató
- Division of Clinical Physiology Institute of Cardiology Research Center for Molecular Medicine Faculty of Medicine University of Debrecen Debrecen Hungary
| | - A. Pető
- Division of Clinical Physiology Institute of Cardiology Research Center for Molecular Medicine Faculty of Medicine University of Debrecen Debrecen Hungary
| | - G. Á. Fülöp
- Division of Clinical Physiology Institute of Cardiology Research Center for Molecular Medicine Faculty of Medicine University of Debrecen Debrecen Hungary
| | - I. Rutkai
- Division of Clinical Physiology Institute of Cardiology Research Center for Molecular Medicine Faculty of Medicine University of Debrecen Debrecen Hungary
| | - E. T. Pásztor
- Division of Clinical Physiology Institute of Cardiology Research Center for Molecular Medicine Faculty of Medicine University of Debrecen Debrecen Hungary
| | - M. Fagyas
- Division of Clinical Physiology Institute of Cardiology Research Center for Molecular Medicine Faculty of Medicine University of Debrecen Debrecen Hungary
| | - J. Kalász
- Division of Clinical Physiology Institute of Cardiology Research Center for Molecular Medicine Faculty of Medicine University of Debrecen Debrecen Hungary
| | - I. Édes
- Division of Clinical Physiology Institute of Cardiology Research Center for Molecular Medicine Faculty of Medicine University of Debrecen Debrecen Hungary
| | - A. Tóth
- Division of Clinical Physiology Institute of Cardiology Research Center for Molecular Medicine Faculty of Medicine University of Debrecen Debrecen Hungary
| | - Z. Papp
- Division of Clinical Physiology Institute of Cardiology Research Center for Molecular Medicine Faculty of Medicine University of Debrecen Debrecen Hungary
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Lu N, Xie S, Li J, Tian R, Peng YY. Myeloperoxidase-mediated oxidation targets serum apolipoprotein A-I in diabetic patients and represents a potential mechanism leading to impaired anti-apoptotic activity of high density lipoprotein. Clin Chim Acta 2015; 441:163-70. [DOI: 10.1016/j.cca.2014.12.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 12/07/2014] [Accepted: 12/10/2014] [Indexed: 12/21/2022]
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Reverri EJ, Morrissey BM, Cross CE, Steinberg FM. Inflammation, oxidative stress, and cardiovascular disease risk factors in adults with cystic fibrosis. Free Radic Biol Med 2014; 76:261-77. [PMID: 25172163 DOI: 10.1016/j.freeradbiomed.2014.08.005] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 07/31/2014] [Accepted: 08/05/2014] [Indexed: 12/21/2022]
Abstract
Cystic fibrosis (CF) represents one of a number of localized lung and non-lung diseases with an intense chronic inflammatory component associated with evidence of systemic oxidative stress. Many of these chronic inflammatory diseases are accompanied by an array of atherosclerotic processes and cardiovascular disease (CVD), another condition strongly related to inflammation and oxidative stress. As a consequence of a dramatic increase in long-lived patients with CF in recent decades, the specter of CVD must be considered in these patients who are now reaching middle age and beyond. Buttressed by recent data documenting that CF patients exhibit evidence of endothelial dysfunction, a recognized precursor of atherosclerosis and CVD, the spectrum of risk factors for CVD in CF is reviewed here. Epidemiological data further characterizing the presence and extent of atherogenic processes in CF patients would seem important to obtain. Such studies should further inform and offer mechanistic insights into how other chronic inflammatory diseases potentiate the processes leading to CVDs.
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Affiliation(s)
- Elizabeth J Reverri
- Department of Nutrition, University of California Davis, One Shields Avenue, 3135 Meyer Hall, Davis, CA 95616, USA
| | - Brian M Morrissey
- Adult Cystic Fibrosis Clinic and Division of Pulmonary-Critical Care Medicine, University of California Davis Medical Center, 4150 V Street, Sacramento, CA 95817, USA
| | - Carroll E Cross
- Adult Cystic Fibrosis Clinic and Division of Pulmonary-Critical Care Medicine, University of California Davis Medical Center, 4150 V Street, Sacramento, CA 95817, USA.
| | - Francene M Steinberg
- Department of Nutrition, University of California Davis, One Shields Avenue, 3135 Meyer Hall, Davis, CA 95616, USA
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Rogowicz-Frontczak A, Pilacinski S, Araszkiewicz A, Zozulinska-Ziolkiewicz D, Wykretowicz A, Wierusz-Wysocka B. C-Reactive protein and soluble intracellular adhesion molecule-1 are related to pulse wave reflection in type 1 diabetes 1C-1. J Diabetes 2014; 6:577-85. [PMID: 24456036 DOI: 10.1111/1753-0407.12129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 11/10/2013] [Accepted: 01/16/2014] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND The association of inflammation with cardiovascular (CV) complications in diabetes remains a matter of considerable debate. Arterial stiffness and enhanced wave reflection play an important role in CV complications. Therefore, in the present study we investigated whether markers of inflammation are correlated with parameters of wave reflection in type 1 diabetes (T1D). METHODS In all, 145 T1D patients were included in the study (median age 32 years, disease duration 10 years, HbA1c 8.2%). Serum concentrations of high-sensitivity C-reactive protein (hs-CRP), matrix metalloproteinase (MMP)-9, soluble intracellular adhesion molecule-1 (sICAM-1), and myeloperoxidase (MPO) were estimated as markers of inflammation. Parameters of pulse wave reflection (central augmentation index [cAIx] and peripheral augmentation index [pAIx]) were assessed using pulse wave analysis. RESULTS Multivariate linear regression analysis revealed that, after adjustment for age, mean blood pressure, HbA1c, low-density lipoprotein-cholesterol, and the presence of at least one microangiopathic complication of diabetes, cAIx and pAIx were associated with serum concentration of hs-CRP (β = 1.838, 95% confidence interval [CI] 0.336-3.339 [P = 0.017]; and β = 2.041, 95% CI 0.683-3.400 [P = 0.004], respectively) and sICAM-1 (β = 0.073, 95% CI 0.015-0.131 [P = 0.014]; and β = 0.066, 95% CI 0.013-0.119 [P = 0.016], respectively) in the study group. CONCLUSIONS In T1D parameters of wave reflection are related to markers of inflammation.
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Affiliation(s)
- Anita Rogowicz-Frontczak
- Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences, Poznan, Poland
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Lu N, Li J, He Y, Tian R, Xiao Q. Nitrative modifications of α-enolase in hepatic proteins from diabetic rats: the involvement of myeloperoxidase. Chem Biol Interact 2014; 220:12-9. [PMID: 24924950 DOI: 10.1016/j.cbi.2014.05.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 05/23/2014] [Accepted: 05/28/2014] [Indexed: 01/15/2023]
Abstract
Many studies reported that oxidative and nitrative stress might be important in the pathogenesis of diabetes and the development of its complications. In this study, we showed that α-enolase (EC 4.2.1.11, 2-phospho-d-glycerate hydrolase) was identified as the important target for oxidative and nitrative modifications in diabetic hepatic proteins. After 6 weeks of streptozotocin-administration, α-enolase expression and nitration were clearly increased in diabetic rat liver, whereas the enolase activity and oxidation status were not significantly changed in diabetic group. By means of immunoprecipitation and liquid chromatography-tandem mass spectrometry analysis, it was found that Tyr 12 and Tyr 257 of α-enolase were the most susceptible to nitration in diabetic rat liver. Moreover, myeloperoxidase (MPO) as a likely alternative mechanism for nitrative modification of α-enolase in vivo was apparently facilitated by the presence of higher MPO level and activity in diabetic liver, and fact that Tyr 12 and Tyr 191 of enolase was nitrated by MPO/nitrite/H2O2 system in vitro. Further studies in vitro indicated that carbonyl formation, rather than tyrosine nitration, might make a major contribution to the inactivation of enolase. The present results provided the new evidence for α-enolase as a susceptive target for MPO-catalyzed nitrative modification in diabetes. They also suggested a potential contribution of nitrative and oxidative modifications of enolase to an impaired glycolytic activity in diabetic hepatic injury.
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Affiliation(s)
- Naihao Lu
- Jiangxi Key Laboratory of Functional Organic Molecules, Jiangxi Science and Technology Normal University, Nanchang 330013, China; Key Laboratory of Functional Small Organic Molecule, Ministry of Education and College of Life Science, Jiangxi Normal University, 99 Ziyang Road, Nanchang, Jiangxi 330022, China.
| | - Jiayu Li
- Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, 99 Ziyang Road, Nanchang, Jiangxi 330022, China
| | - Yingjie He
- Key Laboratory of Functional Small Organic Molecule, Ministry of Education and College of Life Science, Jiangxi Normal University, 99 Ziyang Road, Nanchang, Jiangxi 330022, China; Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, 99 Ziyang Road, Nanchang, Jiangxi 330022, China
| | - Rong Tian
- Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, 99 Ziyang Road, Nanchang, Jiangxi 330022, China
| | - Qiang Xiao
- Jiangxi Key Laboratory of Functional Organic Molecules, Jiangxi Science and Technology Normal University, Nanchang 330013, China.
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Abstract
We described a spectrophotometric method for measuring hemoglobin peroxidase activity in human plasma using o-dianisidine (o-DA) as the substrate and myeloperoxidase specific inhibitor 4-aminobensoic acid hydrazide (ruling out the probable contribution of myeloperoxidase to the measured parameter value). The optimal conditions (pH 5.5; 2 mM H2O2) have been determined, at which hemoglobin makes the main contribution to plasma oxidation of o-DA. A significant positive correlation between hemoglobin peroxidase activity measured by the spectrophotometric method and hemoglobin level measured by the pyridine hemochromogenic method has been detected (r=0.624; p<0.01) in plasma specimens from 16 donors. Plasma hemoglobin peroxidase activities were measured in healthy individuals and patients with type 2 diabetes mellitus and coronary heart disease. High plasma hemoglobin peroxidase activities in both groups of patients indicates disorders in the mechanisms of clearance of hemoglobin and its highly reactive derivatives and can serve as specific markers of diseases associated with oxidative stress.
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40
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Ergen A, Karagedik H, Karaali ZE, Isbir T. An association between MPO -463 G/A polymorphism and type 2 diabetes. Folia Biol (Praha) 2014; 60:108-12. [PMID: 25056433 DOI: 10.14712/fb2014060030108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Myeloperoxidase (MPO) is an enzyme which is a member of the haem-peroxidase superfamily and plays a role in production of reactive oxygen species. The most common polymorphism in the promoter region of MPO gene is -463 G/A. It was shown that carrying the GG genotype means increased activity of the gene approximately 2-3-fold compared to GA and AA genotypes. It was found that hyperglycaemia, modified oxidized proteins and increased advanced glycosylated end products (AGE) are related to oxidative stress in diabetes. Under the hyperglycaemic conditions, production of reactive oxygen radical is elevated in smooth muscle endothelial cells, mesengial and tubular endothelial cells. Especially, elevated lipid oxidation plays an important role in pathogenesis of diabetic complications such as cardiovascular complications. We examined the MPO -463 G/A polymorphism by using the PCR-RFLP method in 145 type 2 diabetic patients and 151 healthy controls. We observed that the AA genotype and A allele were protective variants against type 2 diabetes and the GG genotype was a risk factor for diabetes. While we studied the relationship between genotypes and biochemical parameters, we found that patients with the A allele had decreased serum cholesterol, triglyceride, VLDL levels and body mass index. We suggest that the MPO gene has an important role in pathogenesis of type 2 diabetes because of the increased frequency of GG genotype, which is related to increased activity and oxidant capacity of MPO in the patients.
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Affiliation(s)
- A Ergen
- Istanbul University, The Institute of Experimental Medicine, Department of Molecular Medicine, Capa- Istanbul, Turkey
| | - H Karagedik
- Istanbul University, The Institute of Experimental Medicine, Department of Molecular Medicine, Capa- Istanbul, Turkey
| | - Z E Karaali
- Department of Internal Medicine, Haseki Training and Research Hospital, Istanbul, Turkey
| | - T Isbir
- Department of Medical Biology, Yeditepe University, Faculty of Medicine, Istanbul, Turkey
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Kataoka Y, Shao M, Wolski K, Uno K, Puri R, Murat Tuzcu E, Hazen SL, Nissen SE, Nicholls SJ. Myeloperoxidase levels predict accelerated progression of coronary atherosclerosis in diabetic patients: insights from intravascular ultrasound. Atherosclerosis 2013; 232:377-83. [PMID: 24468151 DOI: 10.1016/j.atherosclerosis.2013.11.075] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Revised: 11/26/2013] [Accepted: 11/27/2013] [Indexed: 12/14/2022]
Abstract
OBJECTIVE While inflammation has been proposed to contribute to the adverse cardiovascular outcome in diabetic patients, the specific pathways involved have not been elucidated. The leukocyte derived product, myeloperoxidase (MPO), has been implicated in all stages of atherosclerosis. The relationship between MPO and accelerated disease progression observed in diabetic patients has not been studied. METHODS We investigated the relationship between MPO and disease progression in diabetic patients. 881 patients with angiographic coronary artery disease underwent serial evaluation of atherosclerotic burden with intravascular ultrasound. Disease progression in diabetic (n = 199) and non-diabetic (n = 682) patients, stratified by baseline MPO levels was investigated. RESULTS MPO levels were similar in patients with and without diabetes (1362 vs. 1255 pmol/L, p = 0.43). No relationship was observed between increasing quartiles of MPO and either baseline (p = 0.81) or serial changes (p = 0.43) in levels of percent atheroma volume (PAV) in non-diabetic patients. In contrast, increasing MPO quartiles were associated with accelerated PAV progression in diabetic patients (p = 0.03). While optimal control of lipid and the use of high-dose statin were associated with less disease progression, a greater benefit was observed in diabetic patients with lower compared with higher MPO levels at baseline. CONCLUSIONS Increasing MPO levels are associated with greater progression of atherosclerosis in diabetic patients. This finding indicates the potential importance of MPO pathways in diabetic cardiovascular disease.
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Affiliation(s)
- Yu Kataoka
- Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
| | - Mingyuan Shao
- Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Kathy Wolski
- Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Kiyoko Uno
- Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Rishi Puri
- Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - E Murat Tuzcu
- Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Stanley L Hazen
- Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Cell Biology, Cleveland Clinic and the Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Steven E Nissen
- Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Stephen J Nicholls
- Department of Cardiovascular Medicine, Heart & Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
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Rojas M, Zhang W, Xu Z, Lemtalsi T, Chandler P, Toque HA, Caldwell RW, Caldwell RB. Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury. PLoS One 2013; 8:e84357. [PMID: 24358357 PMCID: PMC3866146 DOI: 10.1371/journal.pone.0084357] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Accepted: 11/14/2013] [Indexed: 12/11/2022] Open
Abstract
Objective Diabetic retinopathy, a major cause of blindness, is characterized by increased expression of vascular endothelial growth factor (VEGF), leukocyte attachment to the vessel walls and increased vascular permeability. Previous work has shown that reactive oxygen species (ROS) produced by the superoxide generating enzyme NOX2/NADPH oxidase play a crucial role in the vascular pathology. The aim of this work was to identify the cellular sources of the damaging NOX2 activity by studies using bone marrow chimera mice. Methods Bone marrow cells were collected from the femurs and tibias of wild type and NOX2 deficient (NOX2-/-) donor mice and injected intravenously into lethally irradiated NOX2-/- and wild type recipients. Following recovery from radiation, mice were rendered diabetic by streptozotocin injections. The following groups of bone marrow chimeras were studied: non-diabetic WT→WT, diabetic WT→WT, diabetic WT→NOX2-/-, diabetic NOX2-/-→WT. After 4 weeks of diabetes, early signs of retinopathy were examined by measuring ROS, expression of VEGF and ICAM-1, leukocyte attachment to the vessel wall and vascular permeability. Results The retinas of the diabetic WT→WT chimeras showed significant increases in ROS as compared with the non-diabetic chimeras. These diabetes-induced alterations were correlated with increases in expression of VEGF and ICAM-1, leukocyte adhesion and vascular permeability. Each of these diabetes-induced alterations were significantly attenuated in the diabetic WT→NOX2-/- and NOX2-/-→WT chimera groups (p<0.05). Conclusion NOX2-generated ROS produced by both bone marrow-derived cells and resident retinal cells contribute importantly to retinal vascular injury in the diabetic retina. Targeting NOX2 in bone marrow and/or retinal cells may represent a novel therapeutic strategy for the treatment/prevention of vascular injury in the diabetic retina.
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Affiliation(s)
- Modesto Rojas
- VA Medical Center, Augusta, Georgia, United States of America
- Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America
| | - Wenbo Zhang
- VA Medical Center, Augusta, Georgia, United States of America
- Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America
| | - Zhimin Xu
- VA Medical Center, Augusta, Georgia, United States of America
- Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America
| | - Tahira Lemtalsi
- VA Medical Center, Augusta, Georgia, United States of America
- Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America
| | - Phillip Chandler
- Immunotherapy Center, Georgia Reagents University, Augusta, Georgia, United States of America
| | - Haroldo A. Toque
- Department of Pharmacology & Toxicology, Georgia Reagents University, Augusta, Georgia, United States of America
| | - Robert W. Caldwell
- Department of Pharmacology & Toxicology, Georgia Reagents University, Augusta, Georgia, United States of America
| | - Ruth B. Caldwell
- VA Medical Center, Augusta, Georgia, United States of America
- Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America
- * E-mail:
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43
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Rovira-Llopis S, Rocha M, Falcon R, de Pablo C, Alvarez A, Jover A, Hernandez-Mijares A, Victor VM. Is myeloperoxidase a key component in the ROS-induced vascular damage related to nephropathy in type 2 diabetes? Antioxid Redox Signal 2013; 19:1452-1458. [PMID: 23521574 PMCID: PMC3797450 DOI: 10.1089/ars.2013.5307] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 03/24/2013] [Indexed: 11/13/2022]
Abstract
It is still unclear whether microvascular complications of type 2 diabetes correlate with leukocyte-endothelium interactions and/or myeloperoxidase (MPO) levels. In the present study, we found that serum levels of glucose, the rate of ROS and MPO concentration were higher in type 2 diabetic patients. Patients with nephropathy (39.6%) presented higher MPO levels that correlate positively with the albumin/creatinine ratio (r = 0.59, p<0.05). In addition, nephropatic patients showed increased leukocyte-endothelium interactions due to an undermining of polymorphonuclear leukocytes (PMN) rolling velocity and increased rolling flux and adhesion, which was accompanied by a rise in levels of the proinflammatory cytokine tumour necrosis factor alpha (TNFα) and the adhesion molecule E-selectin. Furthermore, MPO levels were positively correlated with PMN rolling flux (r = 0.855, p < 0.01) and adhesion (r = 0.682, p<0.05). Our results lead to the hypothesis that type 2 diabetes induces oxidative stress and an increase in MPO levels and leukocyte-endothelium interactions, and that these effects correlate with the development of nephropathy.
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Affiliation(s)
- Susana Rovira-Llopis
- Fundacion para la Investigacion Sanitaria y Biomedica de la Comunidad Valenciana FISABIO, Endocrinology Service, University Hospital Doctor Peset, Valencia, Spain
- Endocrinology Service, University Hospital Doctor Peset, Valencia, Spain
| | - Milagros Rocha
- Fundacion para la Investigacion Sanitaria y Biomedica de la Comunidad Valenciana FISABIO, Endocrinology Service, University Hospital Doctor Peset, Valencia, Spain
- Endocrinology Service, University Hospital Doctor Peset, Valencia, Spain
- Fundacion para la Investigación (INCLIVA), Universidad de Valencia, Valencia, Spain
| | - Rosa Falcon
- Fundacion para la Investigacion Sanitaria y Biomedica de la Comunidad Valenciana FISABIO, Endocrinology Service, University Hospital Doctor Peset, Valencia, Spain
- Endocrinology Service, University Hospital Doctor Peset, Valencia, Spain
| | - Carmen de Pablo
- Department of Pharmacology and CIBER CB06/04/0071 Research Group, CIBER Hepatic and Digestive Diseases, University of Valencia, Valencia, Spain
| | - Angeles Alvarez
- Department of Pharmacology and CIBER CB06/04/0071 Research Group, CIBER Hepatic and Digestive Diseases, University of Valencia, Valencia, Spain
- Fundación General de la Universidad de Valencia, Valencia, Spain
| | - Ana Jover
- Endocrinology Service, University Hospital Doctor Peset, Valencia, Spain
| | - Antonio Hernandez-Mijares
- Fundacion para la Investigacion Sanitaria y Biomedica de la Comunidad Valenciana FISABIO, Endocrinology Service, University Hospital Doctor Peset, Valencia, Spain
- Endocrinology Service, University Hospital Doctor Peset, Valencia, Spain
- Fundacion para la Investigación (INCLIVA), Universidad de Valencia, Valencia, Spain
- Department of Medicine, University of Valencia, Valencia, Spain
| | - Victor M. Victor
- Fundacion para la Investigacion Sanitaria y Biomedica de la Comunidad Valenciana FISABIO, Endocrinology Service, University Hospital Doctor Peset, Valencia, Spain
- Endocrinology Service, University Hospital Doctor Peset, Valencia, Spain
- Fundacion para la Investigación (INCLIVA), Universidad de Valencia, Valencia, Spain
- Department of Physiology, University of Valencia, Valencia, Spain
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44
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The morphology of the microcirculatory bed in burn shock and its correction with perfluorothane infusion. Bull Exp Biol Med 2013; 155:115-7. [PMID: 23667887 DOI: 10.1007/s10517-013-2094-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The use of perflurothane for correction of burn shock is justified, because it effectively normalizes the microcirculatory bed values and protects the ischemic tissues.
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45
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Barnucz E, Veres G, Hegedűs P, Klein S, Zöller R, Radovits T, Korkmaz S, Horkay F, Merkely B, Karck M, Szabó G. Prolyl-hydroxylase inhibition preserves endothelial cell function in a rat model of vascular ischemia reperfusion injury. J Pharmacol Exp Ther 2013; 345:25-31. [PMID: 23388095 DOI: 10.1124/jpet.112.200790] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Storage protocols of vascular grafts need further improvement against ischemia-reperfusion (IR) injury. Hypoxia elicits a variety of complex cellular responses by altering the activity of many signaling pathways, such as the oxygen-dependent prolyl-hyroxylase domain-containing enzyme (PHD). Reduction of PHD activity during hypoxia leads to stabilization and accumulation of hypoxia inducible factor (HIF) 1α. We examined the effects of PHD inhibiton by dimethyloxalylglycine on the vasomotor responses of isolated rat aorta and aortic vascular smooth muscle cells (VSMCs) in a model of cold ischemia/warm reperfusion. Aortic segments underwent 24 hours of cold ischemic preservation in saline or DMOG (dimethyloxalylglycine)-supplemented saline solution. We investigated endothelium-dependent and -independent vasorelaxations. To simulate IR injury, hypochlorite (NaOCl) was added during warm reperfusion. VSMCs were incubated in NaCl or DMOG solution at 4°C for 24 hours after the medium was changed for a supplied standard medium at 37°C for 6 hours. Apoptosis was assessed using the TUNEL method. Gene expression analysis was performed using quantitative real-time polymerase chain reaction. Cold ischemic preservation and NaOCl induced severe endothelial dysfunction, which was significantly improved by DMOG supplementation (maximal relaxation of aortic segments to acetylcholine: control 95% ± 1% versus NaOCl 44% ± 4% versus DMOG 68% ± 5%). Number of TUNEL-positive cell nuclei was significantly higher in the NaOCl group, and DMOG treatment significantly decreased apoptosis. Inducible heme-oxygenase 1 mRNA expressions were significantly higher in the DMOG group. Pharmacological modulation of oxygen sensing system by DMOG in an in vitro model of vascular IR effectively preserved endothelial function. Inhibition of PHDs could therefore be a new therapeutic avenue for protecting endothelium and vascular muscle cells against IR injury.
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MESH Headings
- Amino Acids, Dicarboxylic/pharmacology
- Animals
- Aorta/drug effects
- Aorta/enzymology
- Aorta/pathology
- Apoptosis/drug effects
- Cell Culture Techniques
- Disease Models, Animal
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/enzymology
- Endothelium, Vascular/pathology
- Enzyme Inhibitors/pharmacology
- Heme Oxygenase-1/biosynthesis
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- In Situ Nick-End Labeling
- Isometric Contraction/drug effects
- Male
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/enzymology
- Muscle, Smooth, Vascular/pathology
- Procollagen-Proline Dioxygenase/antagonists & inhibitors
- RNA, Messenger/biosynthesis
- Rats
- Rats, Sprague-Dawley
- Reperfusion Injury/enzymology
- Reperfusion Injury/pathology
- Reperfusion Injury/prevention & control
- Vasodilation/drug effects
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Affiliation(s)
- Enikő Barnucz
- Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University of Heidelberg, INF 326, 69120 Heidelberg, Germany.
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Gorudko IV, Kostevich AV, Sokolov AV, Konstatinova EÉ, Tsapaeva NL, Mironova EV, Zakharova ET, Vasil'ev VB, Cherenkevich SN, Panasenko AM. [Increased myelopepoxidase activity is a risk factor for ishemic heart disease in patients with diabetes mellitus]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2013; 58:475-84. [PMID: 23413692 DOI: 10.18097/pbmc20125804475] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Using previously developed spectro-photonmetrical method (Bioorg. Khim. 2009. V. 35. pp. 629-639), a significant increase of myeloperoxidase (MPO) activity was found in blood plasma of patients with type 2 diabetes mellitus (DM2) without of cardiovascular complications, as well as with ischemic heart disease (IHD). Plasma MPO concentration measured by an enzyme-linked immunosorbent assay was significantly higher only in blood plasma of patient with DM2 and IHD. A direct and significant correlation between MPO activity and MPO concentration was observed only in blood plasma samples from healthy donors. Increased MPO activity did not correlate with MPO concentration in blood plasma of patients with DM2 and DM2 with IHD. Taken together, these results highlight the necessity for studying of the MPO role in the development of pathological processes to determine both the amount of enzyme and its peroxidase activity in the blood. The proposed approach gives comprehensive information about the relationship between MPO activity and MPO concentration in patient blood. Since the high concentration of MPO is a diagnostically significant parameter in the prediction of endothelial dysfunction and cardiovascular disease development, the obtained results evidence the contribution of MPO-dependent reactions in cardiovascular complications associated with diabetes. MPO activity may serve as an additional diagnostic criterion for determination of risk of IHD in DM patients.
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Goodwill AG, Frisbee JC. Oxidant stress and skeletal muscle microvasculopathy in the metabolic syndrome. Vascul Pharmacol 2012; 57:150-9. [PMID: 22796585 DOI: 10.1016/j.vph.2012.07.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 06/19/2012] [Accepted: 07/04/2012] [Indexed: 01/22/2023]
Abstract
The evolution of the metabolic syndrome in afflicted individuals is, in part, characterized by the development of a severely pro-oxidant state within the vasculature. It has been previously demonstrated by many investigators that this increasingly pro-oxidant state can have severe negative implications for many relevant processes within the vasculature, including the coordination of dilator/constrictor tone or reactivity, the structural adaptations of the vascular wall or distal networks, as well as the integrated regulation of perfusion resistance across and throughout the vascular networks. The purpose of this review article is to present the different sources of oxidant stress within the setting of the metabolic syndrome, the available mechanism for attempts at regulation and the vascular outcomes associated with this condition. It is anticipated that this overview will help readers and investigators to more effectively design experiments and interpret their results within the extremely complicated setting of metabolic syndrome.
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Affiliation(s)
- Adam G Goodwill
- Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV 26506, United States
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48
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Abstract
There is ample empiric evidence to indicate that oxidative stress contributes to the pathogenesis of coronary artery disease and has a key role in the onset and progression of diabetes and its complications. Diabetes leads to depletion of the cellular antioxidant defense system and is associated with an increase in the production of free radicals. Oxidative stress can be the result of multiple pathways. Some of these are related to substrate-driven overproduction of mitochondrial reactive oxygen species, advanced glycation end product formation, glucose autoxidation, and depletion of micronutrients and cellular elements with antioxidative properties. There are numerous observational studies in the literature showing a beneficial outcome of the consumption of antioxidant vitamins. However, the interventional trials portray a different picture. The divide between the robust experimental evidence of the pathogenetic role of increased oxidative load in diabetes and the overwhelming failure of antioxidants to show any health benefits in clinical trials may well be characterized as the "antioxidant paradox."
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The potential usefulness of taurine on diabetes mellitus and its complications. Amino Acids 2011; 42:1529-39. [PMID: 21437784 PMCID: PMC3325402 DOI: 10.1007/s00726-011-0883-5] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2010] [Accepted: 03/04/2011] [Indexed: 10/29/2022]
Abstract
Taurine (2-aminoethanesulfonic acid) is a free amino acid found ubiquitously in millimolar concentrations in all mammalian tissues. Taurine exerts a variety of biological actions, including antioxidation, modulation of ion movement, osmoregulation, modulation of neurotransmitters, and conjugation of bile acids, which may maintain physiological homeostasis. Recently, data is accumulating that show the effectiveness of taurine against diabetes mellitus, insulin resistance and its complications, including retinopathy, nephropathy, neuropathy, atherosclerosis and cardiomyopathy, independent of hypoglycemic effect in several animal models. The useful effects appear due to the multiple actions of taurine on cellular functions. This review summarizes the beneficial effects of taurine supplementation on diabetes mellitus and the molecular mechanisms underlying its effectiveness.
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Wiersma JJ, Verberne HJ, Meuwese MC, Stroes ESG, van Miert JNI, van Eck-Smit BLF, Tijssen JGP, Piek JJ, Trip MD. Myeloperoxidase is not associated with scintigraphic myocardial perfusion abnormalities in type 2 diabetic patients with mild stable anginal complaints. Clin Chim Acta 2011; 412:86-90. [PMID: 20869358 DOI: 10.1016/j.cca.2010.09.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Revised: 09/15/2010] [Accepted: 09/15/2010] [Indexed: 01/20/2023]
Abstract
BACKGROUND MPO, an enzyme of the innate immune system, exhibits pro-atherogenic effects. These include oxidative damage to LDL- and HDL-cholesterol, and promotion of endothelial dysfunction. Recent studies revealed that MPO independently predicts adverse outcomes in patients with chest pain or suspected acute coronary syndrome. We evaluated whether plasma myeloperoxidase (MPO) levels are associated with scintigraphic myocardial perfusion abnormalities, in type 2 diabetic patients with mild anginal complaints. METHODS MPO was measured in plasma samples of 267 patients with diabetes mellitus type 2 and stable angina pectoris complaints (Canadian Cardiovascular Society class I-II/IV) prior to myocardial perfusion scintigraphy (MPS). RESULTS The median plasma level of MPO was 141 pmol/L (IQR 115-171 pmol/L). One-hundred-ninety patients (71%) had perfusion abnormalities on MPS and of these, 138 patients had myocardial ischemia. No relation was found between plasma MPO levels and the scintigraphic myocardial perfusion abnormalities. Even in combination with known other cardiovascular risk factors MPO failed to predict scintigraphic myocardial perfusion abnormalities. CONCLUSIONS MPO levels are not associated with scintigraphic myocardial perfusion abnormalities in type 2 diabetic patients with mild anginal complaints. Therefore, in type 2 diabetic patients MPO is not a useful biomarker to predict hemodynamically significant coronary artery disease.
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Affiliation(s)
- Jacobijne J Wiersma
- Department of Cardiology, Academic Medical Center Amsterdam, The Netherlands.
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