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Diniz TG, de Assis CS, de Sousa BRV, Batista KS, Silva AS, de Queiroga Evangelista IW, Viturino MGM, do Nascimento YM, da Silva EF, Tavares JF, Monteiro MGCA, Dos Santos Fechine CPN, E Silva AL, Persuhn DC. Analysis of metabolites associated with ADIPOQ genotypes in individuals with type 2 diabetes mellitus. Sci Rep 2024; 14:28093. [PMID: 39543306 PMCID: PMC11564893 DOI: 10.1038/s41598-024-79686-4] [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: 06/18/2024] [Accepted: 11/11/2024] [Indexed: 11/17/2024] Open
Abstract
Diabetes mellitus (DM) is a significant public health problem and it is known that the identification of molecular markers involved in glycemic control can impact disease control. Although the rs266729 polymorphism located in the promoter of the adiponectin gene (ADP) has been shown to be a candidate for involvement in glycemic control, the genotypic groups have never been characterized in terms of metabolomic aspects. Objective: Analyze the metabolites present in the rs266729 genotype groups. 127 diabetic individuals were compared according to the rs266729 genotype groups CC and GC + GG (RFLP-PCR). Blood plasma metabolites were classified by nuclear magnetic resonance (NMR), and the metabolic pathways of each group using the MetaboAnalyst tool. Insulin therapy (p = 0.049) was more frequent in the GC + GG rs266729 group. Lactate, alanine, glutamine, aspartate, lipid, lysine, isoleucine, citrulline, cholesterol, and fucose impacted the CC group and aspartate, beta-glucose, glutamate, pyruvate, proline, and 2-oxoglutarate impacted the CG + GG group. The glucose-alanine pathway, malate-aspartate transport, and urea cycle impacted the CC group (D-glucose, glutamic acid, L-alanine, oxoglutaric acid, and pyruvic acid). The glutamine/glutamate ratio is likely to be related to the causes of rs266729 influencing the risk of diabetes.
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Affiliation(s)
- Tainá Gomes Diniz
- Post-Graduate Program in Nutrition Science, Federal University of Paraiba, Joao Pessoa, Brazil
| | | | | | - Kamila Sabino Batista
- Semi Arid National Institute - INSA/MCTI, Campina Grande, Paraíba, CEP: 58434-700, Brazil
| | - Alexandre Sérgio Silva
- Department of Physical Education, Federal University of Paraiba (UFPB), Joao Pessoa, PB, Brazil
| | | | - Marina Gonçalves Monteiro Viturino
- Ophthalmology, Otolaryngology and Oral and Maxillofacial Surgery Unit, Lauro Wanderley University Hospital, Federal University of Paraiba, Joao Pessoa, Brazil
| | - Yuri Mangueira do Nascimento
- Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraiba, Joao Pessoa, Brazil
| | - Evandro Ferreira da Silva
- Institute for Research in Drugs and Medicines - IPeFarM, Federal University of Paraíba, João Pessoa, PB, 58051-900, Brazil
| | - Josean Fechine Tavares
- Institute for Research in Drugs and Medicines - IPeFarM, Federal University of Paraíba, João Pessoa, PB, 58051-900, Brazil
| | | | | | - Anauara Lima E Silva
- Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraiba, Joao Pessoa, Brazil
| | - Darlene Camati Persuhn
- Department of Molecular Biology/CCEN, Federal University of Paraiba (UFPB), Joao Pessoa, PB, Brazil.
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Ma S, Xie X, Yuan R, Xin Q, Miao Y, Leng SX, Chen K, Cong W. Vascular Aging and Atherosclerosis: A Perspective on Aging. Aging Dis 2024; 16:AD.2024.0201-1. [PMID: 38502584 PMCID: PMC11745439 DOI: 10.14336/ad.2024.0201-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 02/01/2024] [Indexed: 03/21/2024] Open
Abstract
Vascular aging (VA) is recognized as a pivotal factor in the development and progression of atherosclerosis (AS). Although various epidemiological and clinical research has demonstrated an intimate connection between aging and AS, the candidate mechanisms still require thorough examination. This review adopts an aging-centric perspective to deepen the comprehension of the intricate relationship between biological aging, vascular cell senescence, and AS. Various aging-related physiological factors influence the physical system's reactions, including oxygen radicals, inflammation, lipids, angiotensin II, mechanical forces, glucose levels, and insulin resistance. These factors cause endothelial dysfunction, barrier damage, sclerosis, and inflammation for VA and promote AS via distinct or shared pathways. Furthermore, the increase of senescent cells inside the vascular tissues, caused by genetic damage, dysregulation, secretome changes, and epigenetic modifications, might be the primary cause of VA.
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Affiliation(s)
- Shudong Ma
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Xuena Xie
- School of Pharmacy, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Rong Yuan
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Qiqi Xin
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Yu Miao
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Sean Xiao Leng
- Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
| | - Keji Chen
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Weihong Cong
- School of Pharmacy, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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Curaj A, Vanholder R, Loscalzo J, Quach K, Wu Z, Jankowski V, Jankowski J. Cardiovascular Consequences of Uremic Metabolites: an Overview of the Involved Signaling Pathways. Circ Res 2024; 134:592-613. [PMID: 38422175 DOI: 10.1161/circresaha.123.324001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2024]
Abstract
The crosstalk of the heart with distant organs such as the lung, liver, gut, and kidney has been intensively approached lately. The kidney is involved in (1) the production of systemic relevant products, such as renin, as part of the most essential vasoregulatory system of the human body, and (2) in the clearance of metabolites with systemic and organ effects. Metabolic residue accumulation during kidney dysfunction is known to determine cardiovascular pathologies such as endothelial activation/dysfunction, atherosclerosis, cardiomyocyte apoptosis, cardiac fibrosis, and vascular and valvular calcification, leading to hypertension, arrhythmias, myocardial infarction, and cardiomyopathies. However, this review offers an overview of the uremic metabolites and details their signaling pathways involved in cardiorenal syndrome and the development of heart failure. A holistic view of the metabolites, but more importantly, an exhaustive crosstalk of their known signaling pathways, is important for depicting new therapeutic strategies in the cardiovascular field.
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Affiliation(s)
- Adelina Curaj
- Institute of Molecular Cardiovascular Research, RWTH Aachen University, Germany (A.C., K.Q., Z.W., V.J., J.J.)
| | - Raymond Vanholder
- Department of Internal Medicine and Pediatrics, Nephrology Section, University Hospital, Ghent, Belgium (R.V.)
| | - Joseph Loscalzo
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.L.)
| | - Kaiseng Quach
- Institute of Molecular Cardiovascular Research, RWTH Aachen University, Germany (A.C., K.Q., Z.W., V.J., J.J.)
| | - Zhuojun Wu
- Institute of Molecular Cardiovascular Research, RWTH Aachen University, Germany (A.C., K.Q., Z.W., V.J., J.J.)
| | - Vera Jankowski
- Institute of Molecular Cardiovascular Research, RWTH Aachen University, Germany (A.C., K.Q., Z.W., V.J., J.J.)
| | - Joachim Jankowski
- Institute of Molecular Cardiovascular Research, RWTH Aachen University, Germany (A.C., K.Q., Z.W., V.J., J.J.)
- Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, the Netherlands (J.J.)
- Aachen-Maastricht Institute for Cardiorenal Disease, RWTH Aachen University, Aachen, Germany (J.J.)
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Denimal D. Carbamylated lipoproteins in diabetes. World J Diabetes 2023; 14:159-169. [PMID: 37035232 PMCID: PMC10075031 DOI: 10.4239/wjd.v14.i3.159] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/27/2022] [Accepted: 02/10/2023] [Indexed: 03/15/2023] Open
Abstract
Diabetic dyslipidemia is characterized by quantitative and qualitative abnor-malities in lipoproteins. In addition to glycation and oxidation, carbamylation is also a post-translational modification affecting lipoproteins in diabetes. Patients with type 2 diabetes (T2D) exhibit higher levels of carbamylated low-density lipoproteins (cLDL) and high-density lipoproteins (cHDL). Accumulating evidence suggests that cLDL plays a role in atherosclerosis in diabetes. cLDL levels have been shown to predict cardiovascular events and all-cause mortality. cLDL facilitates immune cell recruitment in the vascular wall, promotes accumulation of lipids in macrophages, and contributes to endothelial dysf-unction, endothelial nitric oxide-synthase (eNOS) inactivation and endothelial repair defects. Lastly, cLDL induces thrombus formation and platelet aggregation. On the other hand, recent data have demonstrated that cHDL serum level is independently associated with all-cause and cardiovascular-related mortality in T2D patients. This relationship may be causative since the atheroprotective properties of HDL are altered after carbamylation. Thus, cHDL loses the ability to remove cholesterol from macrophages, to inhibit monocyte adhesion and recruitment, to induce eNOS activation and to inhibit apoptosis. Taken together, it seems very likely that the abnormalities in the biological functions of LDL and HDL after carbamylation contribute to atherosclerosis and to the elevated cardiovascular risk in diabetes.
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Affiliation(s)
- Damien Denimal
- Department of Biochemistry, University Hospital of Dijon, Dijon 21079, France
- INSERM LNC UMR1231, University of Burgundy, Dijon 21078, France
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Ahmad S, Tan M, Hamid S. DNA repair mechanisms: Exploring potentials of nutraceutical. J Funct Foods 2023. [DOI: 10.1016/j.jff.2023.105415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
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Rigamonti AE, Frigerio G, Caroli D, De Col A, Cella SG, Sartorio A, Fustinoni S. A Metabolomics-Based Investigation of the Effects of a Short-Term Body Weight Reduction Program in a Cohort of Adolescents with Obesity: A Prospective Interventional Clinical Study. Nutrients 2023; 15:529. [PMID: 36771236 PMCID: PMC9921209 DOI: 10.3390/nu15030529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/10/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
Metabolomics applied to assess the response to a body weight reduction program (BWRP) may generate valuable information concerning the biochemical mechanisms/pathways underlying the BWRP-induced cardiometabolic benefits. The aim of the present study was to establish the BWRP-induced changes in the metabolomic profile that characterizes the obese condition. In particular, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach was used to determine a total of 188 endogenous metabolites in the plasma samples of a cohort of 42 adolescents with obesity (female/male = 32/10; age = 15.94 ± 1.33 year; body mass index standard deviation score (BMI SDS) = 2.96 ± 0.46) who underwent a 3-week BWRP, including hypocaloric diet, physical exercise, nutritional education, and psychological support. The BWRP was capable of significantly improving body composition (e.g., BMI SDS, p < 0.0001), glucometabolic homeostasis (e.g., glucose, p < 0.0001), and cardiovascular function (e.g., diastolic blood pressure, p = 0.016). A total of 64 metabolites were significantly reduced after the intervention (at least p < 0.05), including 53 glycerophospholipids (23 PCs ae, 21 PCs aa, and 9 lysoPCs), 7 amino acids (tyrosine, phenylalanine, arginine, citrulline, tryptophan, glutamic acid, and leucine), the biogenic amine kynurenine, 2 sphingomyelins, and (free) carnitine (C0). On the contrary, three metabolites were significantly increased after the intervention (at least p < 0.05)-in particular, glutamine, trans-4-hydroxyproline, and the octadecenoyl-carnitine (C18:1). In conclusion, when administered to adolescents with obesity, a short-term BWRP is capable of changing the metabolomic profile in the plasma.
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Affiliation(s)
- Antonello E. Rigamonti
- Department of Clinical Sciences and Community Health, University of Milan, 20129 Milan, Italy
| | - Gianfranco Frigerio
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6 Avenue Du Swing, L-4367 Belvaux, Luxembourg
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Diana Caroli
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Alessandra De Col
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Silvano G. Cella
- Department of Clinical Sciences and Community Health, University of Milan, 20129 Milan, Italy
| | - Alessandro Sartorio
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 20145 Milan, Italy
| | - Silvia Fustinoni
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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Zhang W, Zheng J, Zhang J, Li N, Yang X, Fang ZZ, Zhang Q. Associations of serum amino acids related to urea cycle with risk of chronic kidney disease in Chinese with type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14:1117308. [PMID: 36936143 PMCID: PMC10018121 DOI: 10.3389/fendo.2023.1117308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
OBJECTIVE Serum levels of amino acids related to urea cycle are associated with risk of type 2 diabetes mellitus (T2DM). Our study aimed to explore whether serum levels of amino acids related to urea cycle, i.e., arginine, citrulline, and ornithine, are also associated with increased risk of chronic kidney disease (CKD) in T2DM. METHODS We extracted medical records of 1032 consecutive patients with T2DM from the Electronic Administrative System of Liaoning Medical University First Affiliated Hospital (LMUFAH) system from May 2015 to August 2016. Of them, 855 patients with completed data available were used in the analysis. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Serum amino acids were measured by mass spectrometry (MS) technology. Binary logistic regression was performed to obtain odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS 52.3% of the 855 T2DM patients were male, and 143 had CKD. In univariable analysis, high serum citrulline, high ratio of arginine to ornithine, and low ratio of ornithine to citrulline were associated with markedly increased risk of CKD (OR of top vs. bottom tertile: 2.87, 95%CI, 1.79-4.62 & 1.98, 95%CI,1.25-3.14 & 2.56, 95%CI, 1.61-4.07, respectively). In multivariable analysis, the ORs of citrulline and ornithine/citrulline ratio for CKD remained significant (OR of top vs. bottom tertile: 2.22, 95%CI, 1.29-3.82 & 2.24, 1.29-3.87, respectively). CONCLUSIONS In Chinese patients with T2DM, high citrulline and low ornithine/citrulline ratio were associated with increased risk of CKD.
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Affiliation(s)
- Wei Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Jun Zheng
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China
| | - Jikun Zhang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Ninghua Li
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Xilin Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Zhong-Ze Fang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, China
- *Correspondence: Qiang Zhang, ; Zhong-Ze Fang,
| | - Qiang Zhang
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China
- *Correspondence: Qiang Zhang, ; Zhong-Ze Fang,
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Liu T, Wang D, Zhou X, Song J, Yang Z, Shi C, Li R, Zhang Y, Zhang J, Yan J, Zhu X, Li Y, Gong M, Wang C, Yuan C, Cui Y, Wu X. Study on the mechanism of American ginseng extract for treating type 2 diabetes mellitus based on metabolomics. Front Pharmacol 2022; 13:960050. [PMID: 36120310 PMCID: PMC9479495 DOI: 10.3389/fphar.2022.960050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 08/01/2022] [Indexed: 11/29/2022] Open
Abstract
American ginseng extract (AGE) is an efficient and low-toxic adjuvant for type 2 diabetes mellitus (T2DM). However, the metabolic mechanisms of AGE against T2DM remain unknown. In this study, a rat model of T2DM was created and administered for 28 days. Their biological (body weight and serum biochemical indicators) and pathological (pancreatic sections stained with HE) information were collected for further pharmacodynamic evaluation. Moreover, an ultra-performance liquid chromatography–mass spectrometry–based (UHPLC–MS/MS–based) untargeted metabolomics method was used to identify potential biomarkers of serum samples from all rats and related metabolic pathways. The results indicated that body weight, fasting blood glucose (FBG), fasting blood insulin (FINS), blood triglyceride concentration (TG), high-density lipoprotein cholesterol (HDL-C), insulin resistance index (HOMA-IR) and insulin sensitivity index (ISI), and impaired islet cells were significantly improved after the high dose of AGE (H_AGE) and metformin treatment. Metabolomics analysis identified 101 potential biomarkers among which 94 metabolites had an obvious callback. These potential biomarkers were mainly enriched in nine metabolic pathways linked to amino acid metabolism and lipid metabolism. Tryptophan metabolism and glutathione metabolism, as differential metabolic pathways between AGE and metformin for treating T2DM, were further explored. Further analysis of the aforementioned results suggested that the anti-T2DM effect of AGE was closely associated with inflammation, oxidative stress, endothelial dysfunction, dyslipidemia, immune response, insulin resistance, insulin secretion, and T2DM-related complications. This study can provide powerful support for the systematic exploration of the mechanism of AGE against T2DM and a basis for the clinical diagnosis of T2DM.
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Affiliation(s)
- Tiantian Liu
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Dan Wang
- School of Pharmacy, Tianjin Medical University, Tianjin, China
- Department of Pharmacy, Chu Hisen-I Memorial Hospital, Tianjin Medical University, Tianjin, China
| | - Xinfeng Zhou
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Jiayin Song
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Zijun Yang
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Chang Shi
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Rongshan Li
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Yanwen Zhang
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Jun Zhang
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Jiuxing Yan
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Xuehui Zhu
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Ying Li
- Tianjin Neurological Institute, Tianjin Medical University, Tianjin, China
| | - Min Gong
- School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Chongzhi Wang
- Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL, United States
| | - Chunsu Yuan
- Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL, United States
| | - Yan Cui
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- *Correspondence: Yan Cui, ; Xiaohui Wu,
| | - Xiaohui Wu
- School of Pharmacy, Tianjin Medical University, Tianjin, China
- *Correspondence: Yan Cui, ; Xiaohui Wu,
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Zhang L, Shen Y, Wang Z, Li X, Xia W, Su L, Fan X, Wang D. Serum Differentially Expressed Angiogenic Cytokines in Head and Neck Vascular Malformations. J Oral Pathol Med 2022; 51:911-919. [PMID: 35854627 DOI: 10.1111/jop.13335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUNDS Head and neck vascular malformation (HNVM) is a highly complex congenital condition that is difficult to diagnose, monitor, and treat. Therefore, it is critical to explore serum cytokines that may be related to its pathology and prognosis. METHODS An antibody-based microarray was used to examine the expression of 31 angiogenic cytokines in 11 HNVM patients relative to 11 healthy subjects. ELISA was used to verify the results. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the differentially expressed cytokines (DECs). Additionally, we explored the function of DECs in human umbilical vein endothelial cells (HUVECs) in vitro via CCK-8, wound healing, transwell, and tube formation assays. RESULTS Expression of interleukin (IL)-10, matrix metallopeptidase-9 (MMP-9), and vascular endothelial growth factor receptor 2 (VEGF-R2) in HNVM patients was significantly higher, whereas levels of IL-12p40 and angiostatin were significantly lower in HNVM patients relative to healthy controls (P<0.05). However, ELISA only verified that IL-10, MMP-9, VEGF-R2, and IL-12p40 had significant expression changes. Functional enrichment analysis revealed DECs mainly participated in the RAS signalling pathway. Functional studies demonstrated that IL-10, MMP-9, and VEGF-R2 promote cell proliferation, migration, invasion, and tube formation, while IL-12p40 inhibited these processes in HUVECs. CONCLUSIONS The present study not only indicates that IL-10, MMP-9, VEGF-R2 and IL-12p40 may participate in the development of HNVMs but also provides a theoretical basis for the discovery of new targeted molecules in the treatment of HNVMs.
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Affiliation(s)
- Liming Zhang
- Department of Interventional Therapy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China
| | - Yuchen Shen
- Department of Interventional Therapy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China
| | - Zhenfeng Wang
- Department of Interventional Therapy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China
| | - Xiao Li
- Department of Interventional Therapy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China
| | - Weiya Xia
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA
| | - Lixin Su
- Department of Interventional Therapy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China
| | - Xindong Fan
- Department of Interventional Therapy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China
| | - Deming Wang
- Department of Interventional Therapy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China
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Xiang Q, Tian F, Xu J, Du X, Zhang S, Liu L. New insight into dyslipidemia‐induced cellular senescence in atherosclerosis. Biol Rev Camb Philos Soc 2022; 97:1844-1867. [PMID: 35569818 PMCID: PMC9541442 DOI: 10.1111/brv.12866] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 04/18/2022] [Accepted: 04/28/2022] [Indexed: 11/28/2022]
Abstract
Atherosclerosis, characterized by lipid‐rich plaques in the arterial wall, is an age‐related disorder and a leading cause of mortality worldwide. However, the specific mechanisms remain complex. Recently, emerging evidence has demonstrated that senescence of various types of cells, such as endothelial cells (ECs), vascular smooth muscle cells (VSMCs), macrophages, endothelial progenitor cells (EPCs), and adipose‐derived mesenchymal stem cells (AMSCs) contributes to atherosclerosis. Cellular senescence and atherosclerosis share various causative stimuli, in which dyslipidemia has attracted much attention. Dyslipidemia, mainly referred to elevated plasma levels of atherogenic lipids or lipoproteins, or functional impairment of anti‐atherogenic lipids or lipoproteins, plays a pivotal role both in cellular senescence and atherosclerosis. In this review, we summarize the current evidence for dyslipidemia‐induced cellular senescence during atherosclerosis, with a focus on low‐density lipoprotein (LDL) and its modifications, hydrolysate of triglyceride‐rich lipoproteins (TRLs), and high‐density lipoprotein (HDL), respectively. Furthermore, we describe the underlying mechanisms linking dyslipidemia‐induced cellular senescence and atherosclerosis. Finally, we discuss the senescence‐related therapeutic strategies for atherosclerosis, with special attention given to the anti‐atherosclerotic effects of promising geroprotectors as well as anti‐senescence effects of current lipid‐lowering drugs.
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Affiliation(s)
- Qunyan Xiang
- Department of Geriatrics, The Second Xiangya Hospital Central South University Changsha Hunan 410011 PR China
- Institute of Aging and Age‐related Disease Research Central South University Changsha Hunan 410011 PR China
| | - Feng Tian
- Department of Geriatric Cardiology The First Affiliated Hospital of Zhengzhou University Zhengzhou Henan 450000 PR China
| | - Jin Xu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital Central South University Changsha Hunan 410011 PR China
- Research Institute of Blood Lipid and Atherosclerosis Central South University Changsha Hunan 410011 PR China
- Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province Changsha Hunan 410011 PR China
- Cardiovascular Disease Research Center of Hunan Province Changsha Hunan 410011 PR China
| | - Xiao Du
- Department of Cardiovascular Medicine, The Second Xiangya Hospital Central South University Changsha Hunan 410011 PR China
- Research Institute of Blood Lipid and Atherosclerosis Central South University Changsha Hunan 410011 PR China
- Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province Changsha Hunan 410011 PR China
- Cardiovascular Disease Research Center of Hunan Province Changsha Hunan 410011 PR China
| | - Shilan Zhang
- Department of Gastroenterology, The Second Xiangya Hospital Central South University Changsha Hunan 410011 PR China
| | - Ling Liu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital Central South University Changsha Hunan 410011 PR China
- Research Institute of Blood Lipid and Atherosclerosis Central South University Changsha Hunan 410011 PR China
- Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province Changsha Hunan 410011 PR China
- Cardiovascular Disease Research Center of Hunan Province Changsha Hunan 410011 PR China
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Lorey MB, Öörni K, Kovanen PT. Modified Lipoproteins Induce Arterial Wall Inflammation During Atherogenesis. Front Cardiovasc Med 2022; 9:841545. [PMID: 35310965 PMCID: PMC8927694 DOI: 10.3389/fcvm.2022.841545] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/26/2022] [Indexed: 12/15/2022] Open
Abstract
Circulating apolipoprotein B-containing lipoproteins, notably the low-density lipoproteins, enter the inner layer of the arterial wall, the intima, where a fraction of them is retained and modified by proteases, lipases, and oxidizing agents and enzymes. The modified lipoproteins and various modification products, such as fatty acids, ceramides, lysophospholipids, and oxidized lipids induce inflammatory reactions in the macrophages and the covering endothelial cells, initiating an increased leukocyte diapedesis. Lipolysis of the lipoproteins also induces the formation of cholesterol crystals with strong proinflammatory properties. Modified and aggregated lipoproteins, cholesterol crystals, and lipoproteins isolated from human atherosclerotic lesions, all can activate macrophages and thereby induce the secretion of proinflammatory cytokines, chemokines, and enzymes. The extent of lipoprotein retention, modification, and aggregation have been shown to depend largely on differences in the composition of the circulating lipoprotein particles. These properties can be modified by pharmacological means, and thereby provide opportunities for clinical interventions regarding the prevention and treatment of atherosclerotic vascular diseases.
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Affiliation(s)
- Martina B. Lorey
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
- Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Katariina Öörni
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
- Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
- *Correspondence: Katariina Öörni
| | - Petri T. Kovanen
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
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12
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Tian Y, Chang S, Xu J, Gong P, Yu B, Qi J. Investigation of the effective components inhibited macrophage foam cell formation in Ophiopogonis Radix. JOURNAL OF ETHNOPHARMACOLOGY 2022; 283:114678. [PMID: 34563614 DOI: 10.1016/j.jep.2021.114678] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 09/12/2021] [Accepted: 09/22/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ophiopogonis Radix, the commonly used traditional Chinese medicine in clinic for treating cardiovascular diseases, is returned to the stomach, lung and heart meridian. It is reported to nourish yin, moisten lung and is used to treat heart yin deficiency syndromes and asthenia of heart and lung, which indicated that Ophiopogonis Radix may have a protective effect on heart disorders. Atherosclerosisis is an important process in the development of cardiovascular diseases and abnormal lipid deposition induced macrophage foam cells is its crucial foundation. Our previous study showed the extract of Ophiopogonis Radix (EOR) ameliorates atherosclerosis in vitro. However, it may protect against cardiovascular diseases through inhibiting macrophage foam cell formation and its potential effective components and mechanisms are still unclear. AIM OF THE STUDY Our study aimed to investigate the effect of Ophiopogonis Radix on macrophage foam cell formation and its potential active constituents and mechanisms. MATERIALS AND METHODS Ox-LDL induced macrophage cells were employed to evaluate the effect of Ophiopogonis Radix on macrophage foam cell formation. Then the potential active constituents inhibited formation of macrophage foam cells were screened by biospecific cell extraction and its underlying mechanisms were also explored by Western blot. RESULTS The extract of Ophiopogonis Radix was found to significantly inhibit macrophage foam cell formation, evidenced by the decrease of TG and TC and Oil Red O staining analysis in macrophage cells, which indicated that EOR reduced the formation of macrophage foam cells. At the same time, EOR was showed to increase antioxidant capacity in macrophage cells. After treatment with EOR, two potential active components interacted with macrophage foam cells specifically were identified to inhibit macrophage foam cell formation including methylophiopogonanone A and methylophiopogonanone B. Methylophiopogonanone A was then proved to decrease the expression of CD36, Lox-1 and SREBP2, increase the expression of ABCA1 obviously, while the expression of ABCG1 and SREBP1 had no changes. CONCLUSIONS In our study, Ophiopogonis Radix was found to protect against atherosclerosis through suppressing ox-LDL induced macrophage foam cell formation and two potential compounds were identified by biospecific cell extraction including methylophiopogonanone A and methylophiopogonanone B. Moreover, methylophiopogonanone A was proved to inhibit foam cells through reducing uptake, synthesis and increasing efflux, which may provide guidance and reference for application of Ophiopogonis Radix and investigation of the effective components of TCMs.
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Affiliation(s)
- YuShan Tian
- Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.
| | - Shanquan Chang
- Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.
| | - Juntao Xu
- Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.
| | - Puyang Gong
- Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.
| | - BoYang Yu
- Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 2111198, PR China.
| | - Jin Qi
- Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 2111198, PR China.
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Gorisse L, Jaisson S, Piétrement C, Gillery P. Carbamylated Proteins in Renal Disease: Aggravating Factors or Just Biomarkers? Int J Mol Sci 2022; 23:574. [PMID: 35008998 PMCID: PMC8745352 DOI: 10.3390/ijms23010574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Carbamylation is a nonenzymatic post-translational modification resulting from the reaction between cyanate, a urea by-product, and proteins. In vivo and in vitro studies have demonstrated that carbamylation modifies protein structures and functions, triggering unfavourable molecular and cellular responses. An enhanced formation of carbamylation-derived products (CDPs) is observed in pathological contexts, especially during chronic kidney disease (CKD), because of increased blood urea. Significantly, studies have reported a positive correlation between serum CDPs and the evolutive state of renal failure. Further, serum concentrations of carbamylated proteins are characterized as strong predictors of mortality in end-stage renal disease patients. Over time, it is likely that these modified compounds become aggravating factors and promote long-term complications, including cardiovascular disorders and inflammation or immune system dysfunctions. These poor clinical outcomes have led researchers to consider strategies to prevent or slow down CDP formation. Even if growing evidence suggests the involvement of carbamylation in the pathophysiology of CKD, the real relevance of carbamylation is still unclear: is it a causal phenomenon, a metabolic consequence or just a biological feature? In this review, we discuss how carbamylation, a consequence of renal function decline, may become a causal phenomenon of kidney disease progression and how CDPs may be used as biomarkers.
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Affiliation(s)
- Laëtitia Gorisse
- MEDyC Unit CNRS UMR n° 7369, Faculty of Medicine, University of Reims Champagne-Ardenne, 51092 Reims, France; (L.G.); (S.J.); (C.P.)
| | - Stéphane Jaisson
- MEDyC Unit CNRS UMR n° 7369, Faculty of Medicine, University of Reims Champagne-Ardenne, 51092 Reims, France; (L.G.); (S.J.); (C.P.)
- Biochemistry Department, University Hospital of Reims, 51092 Reims, France
| | - Christine Piétrement
- MEDyC Unit CNRS UMR n° 7369, Faculty of Medicine, University of Reims Champagne-Ardenne, 51092 Reims, France; (L.G.); (S.J.); (C.P.)
- Pediatrics Department, University Hospital of Reims, 51092 Reims, France
| | - Philippe Gillery
- MEDyC Unit CNRS UMR n° 7369, Faculty of Medicine, University of Reims Champagne-Ardenne, 51092 Reims, France; (L.G.); (S.J.); (C.P.)
- Biochemistry Department, University Hospital of Reims, 51092 Reims, France
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Cao P, Huang B, Hong M, Jiang Y, Cao R, Chi C, Cao Y, Li S. Association of amino acids related to urea cycle with risk of diabetic nephropathy in two independent cross-sectional studies of Chinese adults. Front Endocrinol (Lausanne) 2022; 13:983747. [PMID: 36157443 PMCID: PMC9492834 DOI: 10.3389/fendo.2022.983747] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/12/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE To investigate the association between amino acids related to the urea cycle and diabetic nephropathy (DN) in two independent cross-sectional studies. METHODS We obtained the medical records of 145 individuals with DN and 596 individuals without DN who attended an annual health examination at Liaoning Medical University First Affiliated Hospital (LMUFAH), China, from May 2015 to August 2016. From April 2018 to April 2019, we collected medical records of another 741 individuals: 338 individuals with DN and 403 individuals without DN from the Second Affiliated Hospital of Dalian Medical University (DALIAN), China. Binary logistic regression was used to obtain the odds ratio (OR) and 95% confidence interval (CI). RESULTS In two independent cross-sectional studies, we observed that citrulline was consistently associated with DN risk [OR (95% CI) of per standard deviation (SD) increase for citrulline in the LMUFAH population: 1.200 (1.006, 1.432); OR (95% CI) of per SD increase for citrulline in the DALIAN population: 1.189 (1.012, 1.396); pooled effect size for citrulline: 1.194 (1.060, 1.345)]. However, ornithine, arginine, and the ratio of arginine to ornithine were consistently unrelated to DN risk, and the ratios of other amino acids in the urea cycle were inconsistently associated with DN risk. CONCLUSIONS Citrulline was consistently associated with DN risk in two independent cross-sectional studies in Chinese adults.
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Affiliation(s)
- Penglong Cao
- Clinical Laboratory, The First Hospital of Dalian Medical University, Dalian, China
| | - Bing Huang
- Research Department, Dalian Innovation Center of Laboratory Medicine Mass Spectrometry Technology, Dalian, China
- Research Department, Clinical Mass Spectrometry Profession Technology Innovation Center of Liaoning Province, Jinzhou, China
- Dalian Innovation Center of Laboratory Medicine Mass Spectrometry Technology, Dalian, China
| | - Mo Hong
- Research Department, Dalian Innovation Center of Laboratory Medicine Mass Spectrometry Technology, Dalian, China
- Research Department, Clinical Mass Spectrometry Profession Technology Innovation Center of Liaoning Province, Jinzhou, China
- Dalian Innovation Center of Laboratory Medicine Mass Spectrometry Technology, Dalian, China
| | - Yuxin Jiang
- Research Department, Dalian Innovation Center of Laboratory Medicine Mass Spectrometry Technology, Dalian, China
- Research Department, Clinical Mass Spectrometry Profession Technology Innovation Center of Liaoning Province, Jinzhou, China
- Dalian Innovation Center of Laboratory Medicine Mass Spectrometry Technology, Dalian, China
| | - Ran Cao
- Research Department, Dalian Innovation Center of Laboratory Medicine Mass Spectrometry Technology, Dalian, China
- Research Department, Clinical Mass Spectrometry Profession Technology Innovation Center of Liaoning Province, Jinzhou, China
- Dalian Innovation Center of Laboratory Medicine Mass Spectrometry Technology, Dalian, China
| | - Chen Chi
- Research Department, Dalian Innovation Center of Laboratory Medicine Mass Spectrometry Technology, Dalian, China
- Research Department, Clinical Mass Spectrometry Profession Technology Innovation Center of Liaoning Province, Jinzhou, China
- Dalian Innovation Center of Laboratory Medicine Mass Spectrometry Technology, Dalian, China
| | - Yunfeng Cao
- Shanghai Institute of Planned Parenthood Research, Shanghai, China
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- *Correspondence: Yunfeng Cao, ; Shijun Li,
| | - Shijun Li
- Clinical Laboratory, The First Hospital of Dalian Medical University, Dalian, China
- *Correspondence: Yunfeng Cao, ; Shijun Li,
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Oxidative distress in aging and age-related diseases: Spatiotemporal dysregulation of protein oxidation and degradation. Biochimie 2021; 195:114-134. [PMID: 34890732 DOI: 10.1016/j.biochi.2021.12.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 12/03/2021] [Accepted: 12/04/2021] [Indexed: 12/31/2022]
Abstract
The concept of oxidative distress had arisen from the assessment of cellular response to high concentrations of reactive species that result from an imbalance between oxidants and antioxidants and cause biomolecular damage. The intracellular distribution and flux of reactive species dramatically change in time and space contributing to the remodeling of the redox landscape and sensitivity of protein residues to oxidants. Here, we hypothesize that compromised spatiotemporal control of generation, conversions, and removal of reactive species underlies protein damage and dysfunction of protein degradation machineries. This leads to the accumulation of oxidatively damaged proteins resulted in an age-dependent decline in the organismal adaptability to oxidative stress. We highlight recent data obtained with the use of various cell cultures, animal models, and patients on irreversible and non-repairable oxidation of key redox-sensitive residues. Multiple reaction products include peptidyl hydroperoxides, alcohols, carbonyls, and carbamoyl moieties as well as Tyr-Tyr, Trp-Tyr, Trp-Trp, Tyr-Cys, His-Lys, His-Arg, and Tyr-Lys cross-links. These lead to protein fragmentation, misfolding, covalent cross-linking, oligomerization, aggregation, and ultimately, causing impaired protein function and turnover. 20S proteasome and autophagy-lysosome pathways are two major types of machinery for the degradation and elimination of oxidatively damaged proteins. Spatiotemporal dysregulation of these pathways under oxidative distress conditions is implicated in aging and age-related disorders such as neurodegenerative and cardiovascular diseases and diabetes. Future investigations in this field allow the discovery of new drugs to target components of dysregulated cell signaling and protein degradation machinery to combat aging and age-related chronic diseases.
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Neuropathy - Exponent of Accelerated Involution in Uremia: The Role of Carbamylation. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2021. [DOI: 10.2478/sjecr-2021-0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Premature loss of functional integrity of the nervous system in chronic renal failure (CRF) as a consequence of persistent biological activities of the general uremic milieu is almost identical to its structural and functional involution during the process of physiological ageing, but disproportionate and independent of chronological age. In the hyperuremic status of CRF (urea - carbamide), forced carbamylation, as a non-enzymatic post-translational modification (NEPTM) of proteins and amino acids, by changing their biological properties and decreasing proteolysis capacity, represents pathogenetic potential of intensified molecular ageing and accelerated, pathological involution. Physiological predisposition and the exposure of neuropathy before complications of other organs and organ systems in CRF, due to the simultaneous and mutually pathogenetically related uremic lesion and the tissue and vascular segment of the nervous system, direct interest towards proteomic analytical techniques of quantification of carbamylated products as biomarkers of uremic neurotoxicity. Hypothetically, identical to the already established applications of other NEPTM products in practice, they have the potential of clinical methodology in the evaluation of uremic neuropathy and its contribution to the general prediction, but also to the change of the conventional CRF classification. In addition, the identification and therapeutic control of the substrate of accelerated involution, responsible for the amplification of not only neurological but also general degenerative processes in CRF, is attractive in the context of the well-known attitude towards aging.
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de Araújo Lira AL, de Fátima Mello Santana M, de Souza Pinto R, Minanni CA, Iborra RT, de Lima AMS, Correa-Giannella ML, Passarelli M, Queiroz MS. Serum albumin modified by carbamoylation impairs macrophage cholesterol efflux in diabetic kidney disease. J Diabetes Complications 2021; 35:107969. [PMID: 34183248 DOI: 10.1016/j.jdiacomp.2021.107969] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 05/05/2021] [Accepted: 05/23/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Abnormalities in lipid metabolism, accumulation of uremic toxins and advanced glycation end products may contribute to worsening atherosclerosis. This study characterized the glycation and carbamoylation profile of serum albumin isolated from individuals with diabetic kidney disease and its influence on cholesterol efflux. MATERIAL AND METHODS 49 patients with type 2 diabetes (T2DM) and different eGFR evaluated glycation and carbamoylation profile by measurement of carboxymethyl lysine (CML) and carbamoylated proteins (CBL) in plasma by ELISA, homocitrulline (HCit) in plasma by colorimetry. In the isolated albumins, we quantified CBL (ELISA) and total AGE and pentosidine by fluorescence. Macrophages were treated with albumin isolated, and 14C-Cholesterol efflux mediated by HDL2 or HDL3 was measured. Kruskal-Wallis test, Jonckheere-Terpstra test and Brunner's posttest were used for comparisons among groups. RESULTS Determination of CML, HCit, CBL in plasma, as total AGE and pentosidine in albumins, did not differ between groups; however, CBL in the isolated albumins was higher in the more advanced stages of CKD (p=0.0414). There was reduction in the 14C-cholesterol efflux after treatment for 18h with albumin isolated from patients with eGFR<60mL/min/1.73m2 compared with control group mediated by HDL2 (p=0.0288) and HDL3 (p<0.0001), as well as when compared with eGFR ≥60mL/min/1.73m2 per HDL2 (p=0.0001) and HDL3 (p<0.0001). Treatment for 48h showed that eGFR<15mL/min/1.73m2 had a lower percentage of 14C-cholesterol efflux mediated by HDL2 compared to control and other CKD groups (p=0.0274). CONCLUSIONS Albumins isolated from individuals with T2DM and eGFR<60mL/min/1.73m2 suffer greater carbamoylation, and they impair the cholesterol efflux mediated by HDL2 and HDL3. In turn, this could promote lipids accumulation in macrophages and disorders in reverse cholesterol transport.
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Affiliation(s)
| | | | - Raphael de Souza Pinto
- Lipids Laboratory (LIM 10), Faculty of Medical Sciences, University of Sao Paulo, Brazil
| | - Carlos André Minanni
- Lipids Laboratory (LIM 10), Faculty of Medical Sciences, University of Sao Paulo, Brazil
| | - Rodrigo Tallada Iborra
- Lipids Laboratory (LIM 10), Faculty of Medical Sciences, University of Sao Paulo, Brazil; Sao Judas Tadeu University, Sao Paulo, Brazil
| | - Adriana Machado Saldiba de Lima
- Lipids Laboratory (LIM 10), Faculty of Medical Sciences, University of Sao Paulo, Brazil; Sao Judas Tadeu University, Sao Paulo, Brazil
| | - Maria Lúcia Correa-Giannella
- Laboratory of Carbohydrates and Radioimuneassays (LIM 18), Clinical Hospital, Medical School, University of Sao Paulo, Sao Paulo, Brazil; Department of Graduation in Medicine, Nove de Julho University (Uninove), Sao Paulo, Brazil
| | - Marisa Passarelli
- Lipids Laboratory (LIM 10), Faculty of Medical Sciences, University of Sao Paulo, Brazil; Department of Graduation in Medicine, Nove de Julho University (Uninove), Sao Paulo, Brazil
| | - Márcia Silva Queiroz
- Endocrinology Division, Internal Medicine Department, University of Sao Paulo Medical School, Sao Paulo, Brazil; Department of Graduation in Medicine, Nove de Julho University (Uninove), Sao Paulo, Brazil.
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Endothelial Progenitor Cells Dysfunctions and Cardiometabolic Disorders: From Mechanisms to Therapeutic Approaches. Int J Mol Sci 2021; 22:ijms22136667. [PMID: 34206404 PMCID: PMC8267891 DOI: 10.3390/ijms22136667] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/10/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic syndrome (MetS) is a cluster of several disorders, such as hypertension, central obesity, dyslipidemia, hyperglycemia, insulin resistance and non-alcoholic fatty liver disease. Despite health policies based on the promotion of physical exercise, the reduction of calorie intake and the consumption of healthy food, there is still a global rise in the incidence and prevalence of MetS in the world. This phenomenon can partly be explained by the fact that adverse events in the perinatal period can increase the susceptibility to develop cardiometabolic diseases in adulthood. Individuals born after intrauterine growth restriction (IUGR) are particularly at risk of developing cardiovascular diseases (CVD) and metabolic disorders later in life. It has been shown that alterations in the structural and functional integrity of the endothelium can lead to the development of cardiometabolic diseases. The endothelial progenitor cells (EPCs) are circulating components of the endothelium playing a major role in vascular homeostasis. An association has been found between the maintenance of endothelial structure and function by EPCs and their ability to differentiate and repair damaged endothelial tissue. In this narrative review, we explore the alterations of EPCs observed in individuals with cardiometabolic disorders, describe some mechanisms related to such dysfunction and propose some therapeutical approaches to reverse the EPCs dysfunction.
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Banerjee J, Roy S, Dhas Y, Mishra N. Senescence-associated miR-34a and miR-126 in middle-aged Indians with type 2 diabetes. Clin Exp Med 2020; 20:149-158. [PMID: 31732824 DOI: 10.1007/s10238-019-00593-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 11/01/2019] [Indexed: 12/16/2022]
Abstract
Rapid urbanization and unhealthy dietary patterns critically increase the risk of type 2 diabetes (T2D) in middle-aged Indians. However, despite recent evidence of senescence-associated microRNAs (SA-miRNAs) in regulating complex pathways of ageing, their expressions in middle-aged Indians with T2D remain unexplored. Hence we aimed to investigate the changes in expressions of SA-miRNAs miR-34a and miR-126 in middle-aged T2D patients. A total of 30 T2D patients and 30 controls were recruited of age 31-50 years. The expressions of plasma miR-34a and miR-126 were determined by quantitative PCR. Oxidized LDL (OxLDL) and malondialdehyde (MDA) levels were quantified using enzyme-linked immunosorbent assay (ELISA). The effect of different glucose concentrations on miR-34a, miR-126, senescence-associated, and oxidative stress-responsive genes were also studied in an in vitro model of mice pancreatic β-cells. MiR-34a was significantly upregulated, whereas miR-126 was nonsignificantly reduced in T2D patients as compared to controls. T2D patients showed elevated levels of oxidative stress markers than controls. Analysis of cultured mice pancreatic β-cells exposed to high glucose showed significant upregulation of miR-34a, miR-126, p53, and superoxide dismutase 2 (SOD2). We found that circulating miR-34a levels and oxidative stress markers levels were elevated in the middle-aged Indians with T2D as compared to controls. The presence of diabetes may aggravate the normal ageing process in the middle-aged Indians. These SA-miRNAs can also be used to check the cellular dysfunctions and ageing of pancreatic β-cells.
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Affiliation(s)
- Joyita Banerjee
- Symbiosis School of Biological Sciences (Formerly Symbiosis School of Biomedical Sciences), Symbiosis International (Deemed University), Lavale, Pune, 412115, India
| | - Swagata Roy
- Symbiosis School of Biological Sciences (Formerly Symbiosis School of Biomedical Sciences), Symbiosis International (Deemed University), Lavale, Pune, 412115, India
| | - Yogita Dhas
- Symbiosis School of Biological Sciences (Formerly Symbiosis School of Biomedical Sciences), Symbiosis International (Deemed University), Lavale, Pune, 412115, India
| | - Neetu Mishra
- Symbiosis School of Biological Sciences (Formerly Symbiosis School of Biomedical Sciences), Symbiosis International (Deemed University), Lavale, Pune, 412115, India.
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Simsek B, Yanar K, Çakatay U. Proatherogenic Importance of Carbamylation-induced Protein Damage and Type 2 Diabetes Mellitus: A Systematic Review. Curr Diabetes Rev 2020; 16:608-618. [PMID: 31914914 DOI: 10.2174/1573399816666200107102918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 10/26/2019] [Accepted: 12/12/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION & BACKGROUND Protein carbamylation is a non-enzymatic and irreversible posttranslational process. It affects functions of numerous enzymes, hormones and receptors playing several roles in diabetes pathogenesis by changing their native structures. Detrimental consequences of oxidative protein damage comprise, but are not limited to glyoxidation, lipoxidation and carbonylation reactions. Since the carbamylated plasma proteins are strongly related to the glycemic control parameters of diabetes, they may have an additive value and emerge as potential biomarkers for the follow up, prognosis and treatment of diabetes mellitus. METHODS & RESULTS To conduct our systematic review, we used PubMed and Semantic Scholar, and used 'Protein carbamylation and diabetes' and 'Protein carbamylation and atherosclerosis' as keywords and looked into about five hundred manuscripts. Manuscripts that are not in English were excluded as well as manuscripts that did not mention carbamylation to maintain the focus of the present article. Similar to glycation, carbamylation is able to alter functions of plasma proteins and their interactions with endothelial cells and has been shown to be involved in the development of atherosclerosis. CONCLUSION At this stage, it seems clear that protein carbamylation leads to worse clinical outcomes. To improve patient care, but maybe more importantly to improve healthcare-prevention, we believe the next stage involves understanding how exactly protein carbamylation leads to worse outcomes and when and in what group of people anti-carbamylation therapies must be employed.
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Affiliation(s)
- Bahadir Simsek
- Cerrahpasa, Cerrahpasa Medical School, Medical Program, 34096, Istanbul, Turkey
| | - Karolin Yanar
- Department of Medical Biochemistry, Cerrahpasa Medical School , Istanbul University, 34096, Istanbul, Turkey
| | - Ufuk Çakatay
- Department of Medical Biochemistry, Cerrahpasa Medical School , Istanbul University, 34096, Istanbul, Turkey
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New Insights into the Roles of Monocytes/Macrophages in Cardiovascular Calcification Associated with Chronic Kidney Disease. Toxins (Basel) 2019; 11:toxins11090529. [PMID: 31547340 PMCID: PMC6784181 DOI: 10.3390/toxins11090529] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/06/2019] [Accepted: 09/09/2019] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular disease (CVD) is an important cause of death in patients with chronic kidney disease (CKD), and cardiovascular calcification (CVC) is one of the strongest predictors of CVD in this population. Cardiovascular calcification results from complex cellular interactions involving the endothelium, vascular/valvular cells (i.e., vascular smooth muscle cells, valvular interstitial cells and resident fibroblasts), and monocyte-derived macrophages. Indeed, the production of pro-inflammatory cytokines and oxidative stress by monocyte-derived macrophages is responsible for the osteogenic transformation and mineralization of vascular/valvular cells. However, monocytes/macrophages show the ability to modify their phenotype, and consequently their functions, when facing environmental modifications. This plasticity complicates efforts to understand the pathogenesis of CVC-particularly in a CKD setting, where both uraemic toxins and CKD treatment may affect monocyte/macrophage functions and thereby influence CVC. Here, we review (i) the mechanisms by which each monocyte/macrophage subset either promotes or prevents CVC, and (ii) how both uraemic toxins and CKD therapies might affect these monocyte/macrophage functions.
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Valdivielso JM, Rodríguez-Puyol D, Pascual J, Barrios C, Bermúdez-López M, Sánchez-Niño MD, Pérez-Fernández M, Ortiz A. Atherosclerosis in Chronic Kidney Disease: More, Less, or Just Different? Arterioscler Thromb Vasc Biol 2019; 39:1938-1966. [PMID: 31412740 DOI: 10.1161/atvbaha.119.312705] [Citation(s) in RCA: 172] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Patients with chronic kidney disease (CKD) are at an increased risk of premature mortality, mainly from cardiovascular causes. The association between CKD on hemodialysis and accelerated atherosclerosis was described >40 years ago. However, more recently, it has been suggested that the increase in atherosclerosis risk is actually observed in early CKD stages, remaining stable thereafter. In this regard, interventions targeting the pathogenesis of atherosclerosis, such as statins, successful in the general population, have failed to benefit patients with very advanced CKD. This raises the issue of the relative contribution of atherosclerosis versus other forms of cardiovascular injury such as arteriosclerosis or myocardial injury to the increased cardiovascular risk in CKD. In this review, the pathophysiogical contributors to atherosclerosis in CKD that are shared with the general population, or specific to CKD, are discussed. The NEFRONA study (Observatorio Nacional de Atherosclerosis en NEFrologia) prospectively assessed the prevalence and progression of subclinical atherosclerosis (plaque in vascular ultrasound), confirming an increased prevalence of atherosclerosis in patients with moderate CKD. However, the adjusted odds ratio for subclinical atherosclerosis increased with CKD stage, suggesting a contribution of CKD itself to subclinical atherosclerosis. Progression of atherosclerosis was closely related to CKD progression as well as to the baseline presence of atheroma plaque, and to higher phosphate, uric acid, and ferritin and lower 25(OH) vitamin D levels. These insights may help design future clinical trials of stratified personalized medicine targeting atherosclerosis in patients with CKD. Future primary prevention trials should enroll patients with evidence of subclinical atherosclerosis and should provide a comprehensive control of all known risk factors in addition to testing any additional intervention or placebo.
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Affiliation(s)
- José M Valdivielso
- From the Vascular & Renal Translational Research Group and UDETMA, IRBLleida. Spanish Research Network for Renal Diseases (RedInRen. ISCIII), Lleida, Spain (J.M.V., M.B.-L.)
| | - Diego Rodríguez-Puyol
- Nephrology Unit, Fundación para la investigación del Hospital Universitario Príncipe de Asturias, RedInRen, Alcalá de Henares, Madrid, Spain (D.R.-P.)
| | - Julio Pascual
- Department of Nephrology, Institute Mar for Medical Research, Hospital del Mar, RedInRen, Barcelona, Spain (J.P., C.B.)
| | - Clara Barrios
- Department of Nephrology, Institute Mar for Medical Research, Hospital del Mar, RedInRen, Barcelona, Spain (J.P., C.B.)
| | - Marcelino Bermúdez-López
- From the Vascular & Renal Translational Research Group and UDETMA, IRBLleida. Spanish Research Network for Renal Diseases (RedInRen. ISCIII), Lleida, Spain (J.M.V., M.B.-L.)
| | - Maria Dolores Sánchez-Niño
- IIS-Fundacion Jimenez Diaz, School of Medicine, University Autonoma of Madrid, FRIAT and RedInRen, Madrid, Spain (M.D.S.-N., A.O.)
| | | | - Alberto Ortiz
- IIS-Fundacion Jimenez Diaz, School of Medicine, University Autonoma of Madrid, FRIAT and RedInRen, Madrid, Spain (M.D.S.-N., A.O.)
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Stankova T, Delcheva G, Maneva A, Vladeva S. Serum Levels of Carbamylated LDL and Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Are Associated with Coronary Artery Disease in Patients with Metabolic Syndrome. MEDICINA (KAUNAS, LITHUANIA) 2019; 55:E493. [PMID: 31443320 PMCID: PMC6722918 DOI: 10.3390/medicina55080493] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/11/2019] [Accepted: 08/13/2019] [Indexed: 01/06/2023]
Abstract
Background and objectives: Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) has been recognized as the primary receptor for carbamylated low-density lipoproteins (cLDL) and is increasingly being viewed as a critical mediator of vascular inflammation and atherosclerosis. The aim of the current study was to evaluate the possible role of circulating cLDL and soluble LOX-1 (sLOX-1) as potential biomarkers of metabolic syndrome (MetS) as well as of coronary artery disease (CAD) among MetS patients. Materials and Methods: The serum levels of cLDL and sLOX-1 were measured by ELISA in 30 MetS patients without CAD, 30 MetS patients with CAD, and 30 healthy controls. Results: Patients with MetS had significantly higher serum levels of both cLDL and sLOX-1 than the healthy controls but lower in comparison to MetS + CAD subjects. Serum sLOX-1 concentration correlated significantly with fasting glucose (rs = 0.414, p = 0.001) and high-density lipoprotein (HDL)-cholesterol (rs = -0.273, p = 0.035) in the whole MetS cohort, whereas it correlated with cLDL only in the MetS + CAD subgroup (rs = 0.396, p = 0.030). The receiver-operating characteristic (ROC) curves of cLDL and sLOX-1 for MetS diagnosis had area under the curve (AUC) values of 0.761 and 0.692, respectively. AUC values of cLDL and sLOX-1 for CAD diagnosis among MetS patients were 0.811 and 0.739. Elevated serum levels of cLDL and sLOX-1 were associated with a higher risk of MetS development [odds ratio (OR) 24.28, 95% confidence interval (CI): 5.86-104.61, p < 0.001 and OR 4.75; 95% CI: 1.58-14.25, p = 0.009] as well as with presence of CAD among MetS subjects (OR 11.23; 95% CI: 3.10-40.71, p < 0.001 and OR 4.03; 95% CI: 1.73-11.84, p = 0.019, respectively). Conclusions: The present study underscores the potential of cLDL and sLOX-1 as promising biomarkers for diagnosis and risk assessment of MetS and CAD among the MetS population.
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Affiliation(s)
- Teodora Stankova
- Department of Biochemistry, Faculty of Pharmacy, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria.
| | - Ginka Delcheva
- Department of Biochemistry, Faculty of Pharmacy, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria
| | - Ana Maneva
- Department of Biochemistry, Faculty of Pharmacy, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria
| | - Stefka Vladeva
- Clinic of Endocrinology and Metabolic Disorders, University Hospital "Kaspela", 4001 Plovdiv, Bulgaria
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24
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Mahmoudi R, Jaisson S, Badr S, Jaidi Y, Bertholon LA, Novella JL, Gillery P. Post-translational modification-derived products are associated with frailty status in elderly subjects. Clin Chem Lab Med 2019; 57:1153-1161. [PMID: 30817296 DOI: 10.1515/cclm-2018-1322] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 02/06/2019] [Indexed: 01/24/2023]
Abstract
Background Identifying frail elderly subjects is of paramount importance in order to conduct a tailored care. The characterization of frailty status is currently based on the collection of clinical data and on the use of various tools such as Fried's criteria, which constitutes a difficult and time-consuming process. Up to now, no biological markers have been described as reliable tools for frailty characterization. We tested the hypothesis that a link between frailty and protein molecular aging existed. This study aimed therefore at determining whether post-translational modification derived products (PTMDPs), recognized as biomarkers of protein aging, were associated with frailty status in elderly subjects. Methods Frailty status was determined according to Fried's criteria in 250 elderly patients (>65 years old) hospitalized in a short-term care unit. Serum concentrations of protein-bound PTMDPs, including carboxymethyllysine (CML), pentosidine, methylglyoxal-hydroimidazolone-1 and homocitrulline (HCit), were determined by liquid chromatography coupled with tandem mass spectrometry, and tissue content of advanced glycation end-products was assessed by skin autofluorescence (SAF) measurement. Associations between PTMDPs and frailty status were analyzed using logistic regression models. Results Frail patients had significantly (p<0.01) higher CML, HCit, and SAF values compared to non-frail and pre-frail subjects. By multivariate analysis, only HCit concentrations and SAF values remained associated with frailty status (p=0.016 and p=0.002, respectively), independently of age, comorbidities, renal function, C-reactive protein and albumin concentrations. Conclusions HCit and SAF are significantly associated with frailty status in elderly subjects. This study suggests that PTMDPs constitute promising biomarkers for identifying frail patients and guiding personalized patient care.
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Affiliation(s)
- Rachid Mahmoudi
- University Hospital of Reims, Department of Internal Medicine and Geriatrics, Maison Blanche Hospital, Reims cedex, France.,University of Reims Champagne-Ardenne, Faculty of Medicine, Reims, France
| | - Stéphane Jaisson
- University of Reims Champagne-Ardenne, Laboratory of Biochemistry and Molecular Biology, MEDyC Unit CNRS/URCA UMR n° 7369, Reims, France.,University Hospital of Reims, Department of Biochemistry-Pharmacology-Toxicology, Reims, France
| | - Sarah Badr
- University Hospital of Reims, Department of Internal Medicine and Geriatrics, Maison Blanche Hospital, Reims cedex, France
| | - Yacine Jaidi
- University Hospital of Reims, Department of Internal Medicine and Geriatrics, Maison Blanche Hospital, Reims cedex, France
| | - Laurie-Anne Bertholon
- University Hospital of Reims, Department of Internal Medicine and Geriatrics, Maison Blanche Hospital, Reims cedex, France
| | - Jean-Luc Novella
- University Hospital of Reims, Department of Internal Medicine and Geriatrics, Maison Blanche Hospital, Reims cedex, France.,University of Reims Champagne-Ardenne, Faculty of Medicine, Reims, France
| | - Philippe Gillery
- University of Reims Champagne-Ardenne, Laboratory of Biochemistry and Molecular Biology, MEDyC Unit CNRS/URCA UMR n° 7369, Reims, France.,University Hospital of Reims, Department of Biochemistry-Pharmacology-Toxicology, Reims, France
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25
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Desmons A, Okwieka A, Doué M, Gorisse L, Vuiblet V, Pietrement C, Gillery P, Jaisson S. Proteasome-dependent degradation of intracellular carbamylated proteins. Aging (Albany NY) 2019; 11:3624-3638. [PMID: 31170093 PMCID: PMC6594819 DOI: 10.18632/aging.102002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 05/27/2019] [Indexed: 12/28/2022]
Abstract
Carbamylation, which corresponds to the binding of isocyanic acid to the amino groups of proteins, is a nonenzymatic post-translational modification responsible for alterations of protein structural and functional properties. Tissue accumulation of carbamylation-derived products and their role in pathological processes such as atherosclerosis or chronic renal failure have been previously documented. However, few studies have focused on the carbamylation of intracellular proteins and their subsequent role in cellular aging. This study aimed to determine the extent of intracellular protein carbamylation, its impact on cell functions and the ability of cells to degrade these modified proteins. Fibroblasts were incubated with cyanate or urea and the carbamylation level was evaluated by immunostaining and homocitrulline quantification. The results showed that carbamylated proteins accumulated intracellularly and that all proteins were susceptible. The presence of intracellular carbamylated proteins did not modify cell proliferation or type I collagen synthesis nor did it induce cell senescence, but it significantly decreased cell motility. Fibroblasts were able to degrade carbamylated proteins through the ubiquitin-proteasome system. In conclusion, intracellular proteins are susceptible to carbamylation but their accumulation does not seem to deeply affect cell function, owing largely to their elimination by the ubiquitin-proteasome system.
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Affiliation(s)
- Aurore Desmons
- Laboratory of Biochemistry and Molecular Biology, CNRS/URCA UMR N° 7369 MEDyC, Faculty of Medicine, University of Reims Champagne-Ardenne, Reims, France
- Laboratory of Pediatric Biology and Research, University Hospital of Reims, Reims, France
| | - Anaïs Okwieka
- Laboratory of Biochemistry and Molecular Biology, CNRS/URCA UMR N° 7369 MEDyC, Faculty of Medicine, University of Reims Champagne-Ardenne, Reims, France
| | - Manon Doué
- Laboratory of Biochemistry and Molecular Biology, CNRS/URCA UMR N° 7369 MEDyC, Faculty of Medicine, University of Reims Champagne-Ardenne, Reims, France
| | - Laëtitia Gorisse
- Laboratory of Biochemistry and Molecular Biology, CNRS/URCA UMR N° 7369 MEDyC, Faculty of Medicine, University of Reims Champagne-Ardenne, Reims, France
- Present address: Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD 20892, USA
| | - Vincent Vuiblet
- Laboratory of Biopathology, University Hospital of Reims, Reims, France
| | - Christine Pietrement
- Laboratory of Biochemistry and Molecular Biology, CNRS/URCA UMR N° 7369 MEDyC, Faculty of Medicine, University of Reims Champagne-Ardenne, Reims, France
- Department of Pediatrics (Nephrology unit), University Hospital of Reims, Reims, France
| | - Philippe Gillery
- Laboratory of Biochemistry and Molecular Biology, CNRS/URCA UMR N° 7369 MEDyC, Faculty of Medicine, University of Reims Champagne-Ardenne, Reims, France
- Laboratory of Pediatric Biology and Research, University Hospital of Reims, Reims, France
| | - Stéphane Jaisson
- Laboratory of Biochemistry and Molecular Biology, CNRS/URCA UMR N° 7369 MEDyC, Faculty of Medicine, University of Reims Champagne-Ardenne, Reims, France
- Laboratory of Pediatric Biology and Research, University Hospital of Reims, Reims, France
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Cao YF, Li J, Zhang Z, Liu J, Sun XY, Feng XF, Luo HH, Yang W, Li SN, Yang X, Fang ZZ. Plasma Levels of Amino Acids Related to Urea Cycle and Risk of Type 2 Diabetes Mellitus in Chinese Adults. Front Endocrinol (Lausanne) 2019; 10:50. [PMID: 30833930 PMCID: PMC6387924 DOI: 10.3389/fendo.2019.00050] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Accepted: 01/21/2019] [Indexed: 12/29/2022] Open
Abstract
Objective: This study aimed to test associations between type 2 diabetes mellitus (T2DM) and metabolites in urea cycle including arginine, citrulline and ornithine. Methods:This study used a hospital-based cross-sectional study design. We retrieved medical notes of 401 in-patients with onset of T2DM within 2 years and 1,522 healthy subjects who attended annual physical examination. All cases were admitted to a tertiary care center in Jinzhou, China from May 2015 to August 2016. Binary logistic regression analyses were performed to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Results:Patients with T2DM had higher arginine, and lower ornithine than control subjects. Levels of citrulline were similar in two groups. Arginine was positively associated with T2DM (ORs: 1.20, 1.17-1.23) while ornithine was negatively associated with T2DM (OR: 0.89, 0.88-0.91). After adjustment for other amino acids and traditional risk factors, these associations were still significant and persistent for arginine and ornithine. The association between citrulline and T2DM was not significant. Their ratios of pairs of two amino acids were associated with increased risk of T2DM. After adjustment for other ratios of amino acids, effect size for T2DM remained significant. Further adjustment for traditional risk factors did not lead to large changes (ORs: 1.78, 1.20-2.65 for the ratio of arginine to ornithine; ORs: 1.59, 1.37-1.86 for the ratio of citrulline to ornithine, respectively) except the ratio of arginine to citrulline. Conclusions: Plasma levels of amino acids related to urea cycle and their ratios of these amino-acids were associated with T2DM in Chinese adults.
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Affiliation(s)
- Yun-Feng Cao
- Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineering Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, China
| | - Jing Li
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Zhipeng Zhang
- Department of Surgery, Peking University Third Hospital, Beijing, China
| | - Jinnan Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Xiao-Yu Sun
- Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China
| | - Xiao-Fei Feng
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Hui-Huan Luo
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Wen Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Sai-Nan Li
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Xilin Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
- *Correspondence: Xilin Yang ;
| | - Zhong-Ze Fang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
- Zhong-Ze Fang
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Xie P, Young MW, Bian H, Niknam-Bienia S, Hong S, Mustoe TA, Galiano RD. Renal dysfunction aggravated impaired cutaneous wound healing in diabetic mice. Wound Repair Regen 2018; 27:49-58. [DOI: 10.1111/wrr.12682] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 10/12/2018] [Accepted: 10/21/2018] [Indexed: 12/27/2022]
Affiliation(s)
- Ping Xie
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Northwestern University Feinberg School of Medicine; Chicago Illinois
| | - Mimi Wu Young
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Northwestern University Feinberg School of Medicine; Chicago Illinois
| | - Huining Bian
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Northwestern University Feinberg School of Medicine; Chicago Illinois
| | - Solmaz Niknam-Bienia
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Northwestern University Feinberg School of Medicine; Chicago Illinois
| | - Seok Hong
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Northwestern University Feinberg School of Medicine; Chicago Illinois
| | - Thomas A Mustoe
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Northwestern University Feinberg School of Medicine; Chicago Illinois
| | - Robert D Galiano
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Northwestern University Feinberg School of Medicine; Chicago Illinois
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Shao Y, Li X, Wood JW, Ma JX. Mitochondrial dysfunctions, endothelial progenitor cells and diabetic retinopathy. J Diabetes Complications 2018; 32:966-973. [PMID: 30068485 DOI: 10.1016/j.jdiacomp.2018.06.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 06/18/2018] [Accepted: 06/28/2018] [Indexed: 12/11/2022]
Abstract
AIM Diabetic retinopathy (DR) is the leading cause of vision loss in the working age population. Endothelial progenitor cells (EPC) play a vital role in vascular damage repair. This article will review recent progress regarding mitochondrial and EPC dysfunction associated with DR. RESULTS EPCs represent a limited population of adult stem cells possessing vasculogenic potential postnatally; their number and function are changed in DR. Among all the function changes, mitochondrial dysfunction plays an important role in the dysregulation of EPCs, as mitochondria regulate energy balance, and cell fate determination. CONCLUSIONS Although the mechanism for the role of mitochondria dysregulation in EPC function remains elusive, mitochondria of EPCs represent a promising target for the treatment of the vasculopathy presented within DR.
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Affiliation(s)
- Yan Shao
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin, China; Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA
| | - Xiaorong Li
- Tianjin Medical University Eye Hospital, Eye Institute & School of Optometry and Ophthalmology, Tianjin, China
| | - John W Wood
- Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA
| | - Jian-Xing Ma
- Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA.
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Abstract
Protein carbamylation is a nonenzymatic posttranslational protein modification that can be driven, in part, by exposure to urea's dissociation product, cyanate. In humans, when kidney function is impaired and urea accumulates, systemic protein carbamylation levels increase. Additional mediators of protein carbamylation have been identified including inflammation, diet, smoking, circulating free amino acid levels, and environmental exposures. Carbamylation reactions on proteins are capable of irreversibly changing protein charge, structure, and function, resulting in pathologic molecular and cellular responses. Carbamylation has been mechanistically linked to the biochemical pathways implicated in atherosclerosis, dysfunctional erythropoiesis, kidney fibrosis, autoimmunity, and other pathological domains highly relevant to patients with chronic kidney disease. In this review, we describe the biochemical impact of carbamylation on human proteins, the mechanistic role carbamylation can have on clinical outcomes in kidney disease, the clinical association studies of carbamylation in chronic kidney disease, including patients on dialysis, and the promise of therapies aimed at reducing carbamylation burden in this vulnerable patient population.
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Affiliation(s)
- Joshua Long
- Nephrology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Xavier Vela Parada
- Nephrology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Sahir Kalim
- Nephrology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
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Haghikia A, Landmesser U. Lipoproteins and Cardiovascular Redox Signaling: Role in Atherosclerosis and Coronary Disease. Antioxid Redox Signal 2018; 29:337-352. [PMID: 28817963 DOI: 10.1089/ars.2017.7052] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
SIGNIFICANCE Lipoproteins, such as low-density lipoprotein, play a causal role in the development of atherosclerosis and coronary disease. Recent Advances: Lipoproteins can stimulate vascular production of reactive oxygen species, which act as important signaling molecules in the cardiovascular system contributing to the pathophysiology of endothelial dysfunction, hypertension, and atherosclerosis. CRITICAL ISSUES Modified lipoproteins have emerged as important regulators of redox signaling, such as oxidized or carbamylated low-density lipoprotein or modified high-density lipoproteins, that contain oxidized lipids, an altered protein cargo, and associated small molecules, such as symmetric dimethylarginine. FUTURE DIRECTIONS In this review, we provide an overview on signaling pathways stimulated by modified lipoproteins in the cardiovascular system and their potential role in cardiovascular disease development. Moreover, we highlight novel aspects of how gut microbiome-related mechanisms-a growing research field-may contribute to lipoprotein modification with subsequent impact on cardiovascular redox signaling. Antioxid. Redox Signal. 29, 337-352.
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Affiliation(s)
- Arash Haghikia
- 1 Department of Cardiology, Charité Universitätsmedizin Berlin , Berlin, Germany
- 2 German Center for Cardiovascular Research (DZHK) , partner site Berlin, Berlin, Germany
| | - Ulf Landmesser
- 1 Department of Cardiology, Charité Universitätsmedizin Berlin , Berlin, Germany
- 2 German Center for Cardiovascular Research (DZHK) , partner site Berlin, Berlin, Germany
- 3 Berlin Institute of Health (BIH) , Berlin, Germany
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31
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Carracedo J, Ramírez-Carracedo R, Martínez de Toda I, Vida C, Alique M, De la Fuente M, Ramírez-Chamond R. Protein Carbamylation: A Marker Reflecting Increased Age-Related Cell Oxidation. Int J Mol Sci 2018; 19:ijms19051495. [PMID: 29772765 PMCID: PMC5983744 DOI: 10.3390/ijms19051495] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 05/14/2018] [Accepted: 05/15/2018] [Indexed: 12/30/2022] Open
Abstract
Carbamylation is a post-translational modification of proteins that may partake in the oxidative stress-associated cell damage, and its increment has been recently proposed as a “hallmark of aging”. The molecular mechanisms associated with aging are related to an increased release of free radicals. We have studied whether carbamylated proteins from the peripheral blood of healthy subjects are related to oxidative damage and aging, taking into account the gender and the immune profile of the subjects. The study was performed in healthy human volunteers. The detection of protein carbamylation and malondialdehyde (MDA) levels was evaluated using commercial kits. The immune profile was calculated using parameters of immune cell function. The results show that the individuals from the elderly group (60–79 years old) have increased carbamylated protein and MDA levels. When considered by gender, only men between 60 and 79 years old showed significantly increased carbamylated proteins and MDA levels. When those subjects were classified by their immune profile, the carbamylated protein levels were higher in those with an older immune profile. In conclusion, the carbamylation of proteins in peripheral blood is related to age-associated oxidative damage and to an aging functional immunological signature. Our results suggest that carbamylated proteins may play an important role at the cellular level in the aging process.
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Affiliation(s)
- Julia Carracedo
- Department of Genetics, Physiology, and Microbiology, Faculty of Biology, Complutense University/Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28040 Madrid, Spain.
| | - Rafael Ramírez-Carracedo
- Cardiovascular Joint Research Unit, Francisco de Vitoria University/Hospital Ramon y Cajal Research Unit (IRYCIS), 28223 Madrid, Spain.
| | - Irene Martínez de Toda
- Department of Genetics, Physiology, and Microbiology, Faculty of Biology, Complutense University/Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28040 Madrid, Spain.
| | - Carmen Vida
- Department of Genetics, Physiology, and Microbiology, Faculty of Biology, Complutense University/Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28040 Madrid, Spain.
| | - Matilde Alique
- Biology Systems Department, Physiology, Alcala University, Alcala de Henares, 28805 Madrid, Spain.
| | - Mónica De la Fuente
- Department of Genetics, Physiology, and Microbiology, Faculty of Biology, Complutense University/Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28040 Madrid, Spain.
| | - Rafael Ramírez-Chamond
- Biology Systems Department, Physiology, Alcala University, Alcala de Henares, 28805 Madrid, Spain.
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Jaisson S, Pietrement C, Gillery P. Protein Carbamylation: Chemistry, Pathophysiological Involvement, and Biomarkers. Adv Clin Chem 2018; 84:1-38. [PMID: 29478512 DOI: 10.1016/bs.acc.2017.12.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Protein carbamylation refers to a nonenzymatic modification, which consists in the binding of isocyanic acid on protein functional groups. This reaction is responsible for the alteration in structural and functional properties of proteins, which participate in their molecular aging. Protein molecular aging is now considered a molecular substratum for the development of chronic and inflammatory diseases, including atherosclerosis, chronic kidney disease, or rheumatoid arthritis. As a consequence, carbamylation-derived products have been proposed as interesting biomarkers in various pathological contexts and appropriate analytical methods have been developed for their quantification in biological fluids. The purpose of this review is (i) to describe the biochemical bases of the carbamylation reaction, (ii) to explain how it contributes to protein molecular aging, (iii) to provide evidence of its involvement in aging and chronic diseases, and (iv) to list the available biomarkers of carbamylation process and the related analytical methods.
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Tian R, Zhang LN, Zhang TT, Pang HY, Chen LF, Shen ZJ, Liu Z, Fang Q, Zhang SY. Association Between Oxidative Stress and Peripheral Leukocyte Telomere Length in Patients with Premature Coronary Artery Disease. Med Sci Monit 2017; 23:4382-4390. [PMID: 28892468 PMCID: PMC5604488 DOI: 10.12659/msm.902106] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Background Leukocyte telomere length (LTL) is regarded as a potential marker of biological aging. Oxidative stress plays a major role in the rate of telomeric DNA loss. The aim of this study was to explore whether the LTL was shorter in Chinese patients with premature coronary artery disease (PCAD) than in non-CAD controls and to determine the relationship between oxidative stress and LTL shortening in this population. Material/Methods Patients for coronary angiography were recruited. In total, 128 patients with PCAD and 128 non-CAD controls were enrolled. Samples of circulating leukocytes and plasma were collected. The mean LTL was measured using a polymerase chain reaction-based assay and expressed as the ratio of telomere repeat copies to single-copy gene (SCG) copies (T/S ratio). Reactive oxygen species (ROS) levels and total antioxidant capacity (T-AOC) were determined in plasma. Results Both the T/S ratio (0.88±0.86 vs. 1.10±0.57, P=0.015) and telomere base pairs (4.97±1.37 kb vs. 5.32±0.91 kb, P=0.015) were significantly shorter in the PCAD group than in non-CAD controls. The T-AOC levels of the PCAD group were significantly lower than those of the non-CAD controls (0.482 mM [0.279, 0.603 mM]) vs. 0.778 mM [0.421, 0.924 mM], P=0.000). The ratio of T-AOC to ROS in the PCAD patients was significantly decreased compared to that of the non-CAD controls (0.1026±0. 1587 [Mm*ml/ng] vs. 0.1435±0.1946 [Mm*ml/ng], P=0.013). Conclusion The results point to a potential link between reduced LTLs in patients with PCAD and early onset of atherosclerosis. The decline in antioxidant capacity may play an important role in accelerating the attrition of telomeres in PCAD patients.
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Affiliation(s)
- Ran Tian
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Lei-Nan Zhang
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Ting-Ting Zhang
- Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Hai-Yu Pang
- Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Lian-Feng Chen
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Zhu-Jun Shen
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Zhenyu Liu
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Quan Fang
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China (mainland)
| | - Shu-Yang Zhang
- Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China (mainland)
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Mistriotis P, Andreadis ST. Vascular aging: Molecular mechanisms and potential treatments for vascular rejuvenation. Ageing Res Rev 2017; 37:94-116. [PMID: 28579130 DOI: 10.1016/j.arr.2017.05.006] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Revised: 05/22/2017] [Accepted: 05/25/2017] [Indexed: 12/14/2022]
Abstract
Aging is the main risk factor contributing to vascular dysfunction and the progression of vascular diseases. In this review, we discuss the causes and mechanisms of vascular aging at the tissue and cellular level. We focus on Endothelial Cell (EC) and Smooth Muscle Cell (SMC) aging due to their critical role in mediating the defective vascular phenotype. We elaborate on two categories that contribute to cellular dysfunction: cell extrinsic and intrinsic factors. Extrinsic factors reflect systemic or environmental changes which alter EC and SMC homeostasis compromising vascular function. Intrinsic factors induce EC and SMC transformation resulting in cellular senescence. Replenishing or rejuvenating the aged/dysfunctional vascular cells is critical to the effective repair of the vasculature. As such, this review also elaborates on recent findings which indicate that stem cell and gene therapies may restore the impaired vascular cell function, reverse vascular aging, and prolong lifespan.
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Affiliation(s)
- Panagiotis Mistriotis
- Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Amherst, NY 14260-4200, USA
| | - Stelios T Andreadis
- Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Amherst, NY 14260-4200, USA; Department of Biomedical Engineering, University at Buffalo, The State University of New York, Amherst, NY 14260-4200, USA; Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY 14203, USA.
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Delanghe S, Delanghe JR, Speeckaert R, Van Biesen W, Speeckaert MM. Mechanisms and consequences of carbamoylation. Nat Rev Nephrol 2017; 13:580-593. [PMID: 28757635 DOI: 10.1038/nrneph.2017.103] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Protein carbamoylation is a non-enzymatic post-translational modification that binds isocyanic acid, which can be derived from the dissociation of urea or from the myeloperoxidase-mediated catabolism of thiocyanate, to the free amino groups of a multitude of proteins. Although the term 'carbamoylation' is usually replaced by the term "carbamylation" in the literature, carbamylation refers to a different chemical reaction (the reversible interaction of CO2 with α and ε-amino groups of proteins). Depending on the altered molecule (for example, collagen, erythropoietin, haemoglobin, low-density lipoprotein or high-density lipoprotein), carbamoylation can have different pathophysiological effects. Carbamoylated proteins have been linked to atherosclerosis, lipid metabolism, immune system dysfunction (such as inhibition of the classical complement pathway, inhibition of complement-dependent rituximab cytotoxicity, reduced oxidative neutrophil burst, and the formation of anti-carbamoylated protein antibodies) and renal fibrosis. In this Review, we discuss the carbamoylation process and evaluate the available biomarkers of carbamoylation (for example, homocitrulline, the percentage of carbamoylated albumin, carbamoylated haemoglobin, and carbamoylated low-density lipoprotein). We also discuss the relationship between carbamoylation and the occurrence of cardiovascular events and mortality in patients with chronic kidney disease and assess the effects of strategies to lower the carbamoylation load.
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Affiliation(s)
- Sigurd Delanghe
- Department of Nephrology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
| | - Joris R Delanghe
- Department of Clinical Chemistry, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
| | - Reinhart Speeckaert
- Department of Clinical Chemistry, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
| | - Wim Van Biesen
- Department of Nephrology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
| | - Marijn M Speeckaert
- Department of Nephrology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
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Rudenko TE, Bobkova IN, Kamyshova ES, Gorelova IA. [Role of the mechanisms of replicative cellular senescence in structural and functional changes of the vascular wall in chronic kidney disease]. TERAPEVT ARKH 2017; 89:102-109. [PMID: 28745697 DOI: 10.17116/terarkh2017896102-109] [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: 11/18/2022]
Abstract
This review considers the mechanisms and risk factors for the development of replicative cellular senescence of the vascular wall in patients with CKD and discusses therapeutic approaches to slowing the accelerated vascular aging.
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Affiliation(s)
- T E Rudenko
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
| | - I N Bobkova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
| | - E S Kamyshova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
| | - I A Gorelova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
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Chistiakov DA, Melnichenko AA, Orekhov AN, Bobryshev YV. How do macrophages sense modified low-density lipoproteins? Int J Cardiol 2017; 230:232-240. [DOI: 10.1016/j.ijcard.2016.12.164] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 12/19/2016] [Accepted: 12/25/2016] [Indexed: 01/18/2023]
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Sandhu K, Mamas M, Butler R. Endothelial progenitor cells: Exploring the pleiotropic effects of statins. World J Cardiol 2017; 9:1-13. [PMID: 28163831 PMCID: PMC5253189 DOI: 10.4330/wjc.v9.i1.1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 08/29/2016] [Accepted: 11/02/2016] [Indexed: 02/07/2023] Open
Abstract
Statins have become a cornerstone of risk modification for ischaemic heart disease patients. A number of studies have shown that they are effective and safe. However studies have observed an early benefit in terms of a reduction in recurrent infarct and or death after a myocardial infarction, prior to any significant change in lipid profile. Therefore, pleiotropic mechanisms, other than lowering lipid profile alone, must account for this effect. One such proposed pleiotropic mechanism is the ability of statins to augment both number and function of endothelial progenitor cells. The ability to augment repair and maintenance of a functioning endothelium may have profound beneficial effect on vascular repair and potentially a positive impact on clinical outcomes in patients with cardiovascular disease. The following literature review will discuss issues surrounding endothelial progenitor cell (EPC) identification, role in vascular repair, factors affecting EPC numbers, the role of statins in current medical practice and their effects on EPC number.
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Florens N, Calzada C, Lyasko E, Juillard L, Soulage CO. Modified Lipids and Lipoproteins in Chronic Kidney Disease: A New Class of Uremic Toxins. Toxins (Basel) 2016; 8:E376. [PMID: 27999257 PMCID: PMC5198570 DOI: 10.3390/toxins8120376] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 12/09/2016] [Accepted: 12/12/2016] [Indexed: 02/07/2023] Open
Abstract
Chronic kidney disease (CKD) is associated with an enhanced oxidative stress and deep modifications in lipid and lipoprotein metabolism. First, many oxidized lipids accumulate in CKD and were shown to exert toxic effects on cells and tissues. These lipids are known to interfere with many cell functions and to be pro-apoptotic and pro-inflammatory, especially in the cardiovascular system. Some, like F2-isoprostanes, are directly correlated with CKD progression. Their accumulation, added to their noxious effects, rendered their nomination as uremic toxins credible. Similarly, lipoproteins are deeply altered by CKD modifications, either in their metabolism or composition. These impairments lead to impaired effects of HDL on their normal effectors and may strongly participate in accelerated atherosclerosis and failure of statins in end-stage renal disease patients. This review describes the impact of oxidized lipids and other modifications in the natural history of CKD and its complications. Moreover, this review focuses on the modifications of lipoproteins and their impact on the emergence of cardiovascular diseases in CKD as well as the appropriateness of considering them as actual mediators of uremic toxicity.
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Affiliation(s)
- Nans Florens
- CarMeN, INSERM U1060, INRA U1397, INSA de Lyon, Université Claude Bernard Lyon 1, University of Lyon, F-69621 Villeurbanne, France.
- Hospices Civils de Lyon, Department of Nephrology, Hôpital E. Herriot, F-69003 Lyon, France.
| | - Catherine Calzada
- CarMeN, INSERM U1060, INRA U1397, INSA de Lyon, Université Claude Bernard Lyon 1, University of Lyon, F-69621 Villeurbanne, France.
| | - Egor Lyasko
- CarMeN, INSERM U1060, INRA U1397, INSA de Lyon, Université Claude Bernard Lyon 1, University of Lyon, F-69621 Villeurbanne, France.
| | - Laurent Juillard
- CarMeN, INSERM U1060, INRA U1397, INSA de Lyon, Université Claude Bernard Lyon 1, University of Lyon, F-69621 Villeurbanne, France.
- Hospices Civils de Lyon, Department of Nephrology, Hôpital E. Herriot, F-69003 Lyon, France.
| | - Christophe O Soulage
- CarMeN, INSERM U1060, INRA U1397, INSA de Lyon, Université Claude Bernard Lyon 1, University of Lyon, F-69621 Villeurbanne, France.
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Sun JT, Yang K, Mao JY, Shen WF, Lu L, Wu QH, Wang YP, Wu LP, Zhang RY. Cyanate-Impaired Angiogenesis: Association With Poor Coronary Collateral Growth in Patients With Stable Angina and Chronic Total Occlusion. J Am Heart Assoc 2016; 5:JAHA.116.004700. [PMID: 27986757 PMCID: PMC5210395 DOI: 10.1161/jaha.116.004700] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Background Cyanate has recently gained attention for its role in the pathogenesis of vascular injury. Nonetheless, the effect of cyanate on angiogenesis remains unclear. Methods and Results In this study, we demonstrated that oral administration of cyanate impaired blood perfusion recovery in a mouse hind‐limb ischemia model. A reduction in blood perfusion recovery at day 21 was observed in the ischemic tissue of cyanate‐treated mice. Likewise, there were fewer capillaries in the ischemic hind‐limb tissue of cyanate‐exposed mice. Our in vitro study showed that cyanate, together with its carbamylated products, inhibited the migration, proliferation, and tube‐formation abilities of endothelial cells. Further research revealed that cyanate regulated angiogenesis partly by interrupting the vascular endothelial growth factor receptor 2/phosphatidylinositol 3‐kinase/Akt pathway. The serum concentrations of homocitrulline, a marker of cyanate exposure, were determined in 117 patients with stable angina and chronic total occlusion. Consistent with the antiangiogenic role of cyanate, homocitrulline levels were increased in patients with poor coronary collateralization (n=58) compared with those with high collateralization (n=59; 21.09±13.08 versus 15.54±9.02 ng/mL, P=0.009). In addition, elevated homocitrulline concentration was a strong predictor of poor coronary collateral growth. Conclusions Impaired angiogenesis induced by cyanate might contribute to poor coronary collateral growth.
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Affiliation(s)
- Jia Teng Sun
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ke Yang
- Institute of Cardiovascular Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Yan Mao
- Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China
| | - Wei Feng Shen
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Institute of Cardiovascular Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Lu
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Hong Wu
- Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Ping Wang
- Institute of Cardiovascular Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Ping Wu
- Institute of Cardiovascular Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rui Yan Zhang
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Bose C, Shah SV, Karaduta OK, Kaushal GP. Carbamylated Low-Density Lipoprotein (cLDL)-Mediated Induction of Autophagy and Its Role in Endothelial Cell Injury. PLoS One 2016; 11:e0165576. [PMID: 27973558 PMCID: PMC5156412 DOI: 10.1371/journal.pone.0165576] [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: 08/15/2016] [Accepted: 10/13/2016] [Indexed: 01/08/2023] Open
Abstract
Patients with chronic kidney disease (CKD) have high risk of cardiovascular complications. Plasma levels of carbamylated proteins produced by urea-derived isocyanate or thiocyanate are elevated in CKD patients and that they are significant predictors of cardiovascular events and all-cause mortality. Carbamylated LDL (cLDL) has pro-atherogenic properties and is known to affect major biological processes relevant to atherosclerosis including endothelial cell injury. The underlying mechanisms of cLDL-induced endothelial cell injury are not well understood. Although autophagy has been implicated in atherosclerosis, cLDL-mediated induction of autophagy and its role in endothelial cell injury is unknown. Our studies demonstrate that human coronary artery endothelial cells (HCAECs) respond to cLDL by specific induction of key autophagy proteins including LC3-I, beclin-1, Atg5, formation of lipid-conjugated LC3-II protein, and formation of punctate dots of autophagosome-associated LC3-II. We demonstrated that autophagy induction is an immediate response to cLDL and occurred in a dose and time-dependent manner. Inhibition of cLDL-induced autophagy by a specific siRNA to LC3 as well as by an autophagy inhibitor provided protection from cLDL-induced cell death and DNA fragmentation. Our studies demonstrate that autophagy plays an important role in cLDL-mediated endothelial cell injury and may provide one of the underlying mechanisms for the pathogenesis of cLDL-induced atherosclerosis in CKD patients.
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Affiliation(s)
- Chhanda Bose
- Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America
- University of Arkansas for Medical Sciences, Department of Internal Medicine, Little Rock, Arkansas, United States of America
| | - Sudhir V. Shah
- Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America
- University of Arkansas for Medical Sciences, Department of Internal Medicine, Little Rock, Arkansas, United States of America
| | - Oleg K. Karaduta
- University of Arkansas for Medical Sciences, Department of Biochemistry, Little Rock, Arkansas, United States of America
| | - Gur P. Kaushal
- Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America
- University of Arkansas for Medical Sciences, Department of Internal Medicine, Little Rock, Arkansas, United States of America
- University of Arkansas for Medical Sciences, Department of Biochemistry, Little Rock, Arkansas, United States of America
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Abstract
The historical view of vascular smooth muscle cells (VSMCs) in atherosclerosis is that aberrant proliferation of VSMCs promotes plaque formation, but that VSMCs in advanced plaques are entirely beneficial, for example preventing rupture of the fibrous cap. However, this view has been based on ideas that there is a homogenous population of VSMCs within the plaque, that can be identified separate from other plaque cells (particularly macrophages) using standard VSMC and macrophage immunohistochemical markers. More recent genetic lineage tracing studies have shown that VSMC phenotypic switching results in less-differentiated forms that lack VSMC markers including macrophage-like cells, and this switching directly promotes atherosclerosis. In addition, VSMC proliferation may be beneficial throughout atherogenesis, and not just in advanced lesions, whereas VSMC apoptosis, cell senescence, and VSMC-derived macrophage-like cells may promote inflammation. We review the effect of embryological origin on VSMC behavior in atherosclerosis, the role, regulation and consequences of phenotypic switching, the evidence for different origins of VSMCs, and the role of individual processes that VSMCs undergo in atherosclerosis in regard to plaque formation and the structure of advanced lesions. We think there is now compelling evidence that a full understanding of VSMC behavior in atherosclerosis is critical to identify therapeutic targets to both prevent and treat atherosclerosis.
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Affiliation(s)
- Martin R Bennett
- From the Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom (M.R.B., S.S.); and University of Virginia School of Medicine, Charlottesville (G.K.O.).
| | - Sanjay Sinha
- From the Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom (M.R.B., S.S.); and University of Virginia School of Medicine, Charlottesville (G.K.O.)
| | - Gary K Owens
- From the Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom (M.R.B., S.S.); and University of Virginia School of Medicine, Charlottesville (G.K.O.)
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Massy ZA, Pietrement C, Touré F. Reconsidering the Lack of Urea Toxicity in Dialysis Patients. Semin Dial 2016; 29:333-7. [DOI: 10.1111/sdi.12515] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Ziad A. Massy
- Division of Nephrology; Ambroise Paré Hospital; APHP; Versailles Saint-Quentin-en-Yvelines University (Paris-Ile-de-France-Ouest University, UVSQ); Boulogne Billancourt/Paris France
- Inserm U-1018 Team 5; Paris-Saclay University and UVSQ; Villejuif France
| | - Christine Pietrement
- Department of Pediatrics; Nephrology Unit; University Hospital of Reims; Reims France
- Laboratoire de Biochimie et de biologie moléculaire; Faculté de médecine; Université de Reims Champagne-Ardenne; CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC); Reims France
| | - Fatouma Touré
- Laboratoire de néphrologie; Faculté de médecine; Université de Reims Champagne-Ardenne; CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC); Reims France
- Division of Nephrology; CHU Reims; Reims France
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Tie G, Yan J, Messina JA, Raffai RL, Messina LM. Inhibition of p38 Mitogen-Activated Protein Kinase Enhances the Apoptosis Induced by Oxidized Low-Density Lipoprotein in Endothelial Progenitor Cells. J Vasc Res 2016; 52:361-71. [PMID: 27031525 DOI: 10.1159/000443889] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Accepted: 01/10/2016] [Indexed: 11/19/2022] Open
Abstract
Oxidized low-density lipoprotein (oxLDL) is an important risk factor in the development of atherosclerosis. oxLDL has been shown to decrease endothelial progenitor cell (EPC) number by inducing apoptosis. p38 mitogen-activated protein kinase (MAPK) was shown to be activated by oxLDL and participated in the regulation of EPC number and function. However, the role of p38 remains unknown. Here, we show that oxLDL-induced p38 phosphorylation in EPCs is time and dose dependent. Treatment with antioxidant N-acetyl cysteine restored oxLDL-induced p38 phosphorylation to basal levels. LOX-1-blocking antibody also significantly decreased oxLDL-induced p38 phosphorylation. Interestingly, TUNEL staining showed that pretreatment with the p38 inhibitor SB203580 further increased oxLDL-induced apoptosis in EPCs. In accordance with these findings, pretreatment with SB203580 further attenuated Akt phosphorylation in EPCs challenged with oxLDL, indicating an interaction between Akt and p38 MAPK pathways. In agreement, inhibition of p38 MAPK further attenuated Akt phosphorylation and increased apoptosis in EPCs isolated from hypercholesterolemic ApoE-/- mice. In conclusion, p38 MAPK serves as an anti-apoptotic pathway by supporting Akt activity when EPCs are challenged with oxLDL.
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Affiliation(s)
- Guodong Tie
- Division of Vascular Surgery, University of Massachusetts Medical School, Worcester, Mass., USA
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Zhi K, Li M, Bai J, Wu Y, Zhou S, Zhang X, Qu L. Quercitrin treatment protects endothelial progenitor cells from oxidative damage via inducing autophagy through extracellular signal-regulated kinase. Angiogenesis 2016; 19:311-24. [DOI: 10.1007/s10456-016-9504-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 03/01/2016] [Indexed: 12/31/2022]
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Luna C, Alique M, Navalmoral E, Noci MV, Bohorquez-Magro L, Carracedo J, Ramírez R. Aging-associated oxidized albumin promotes cellular senescence and endothelial damage. Clin Interv Aging 2016; 11:225-36. [PMID: 27042026 PMCID: PMC4780186 DOI: 10.2147/cia.s91453] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Increased levels of oxidized proteins with aging have been considered a cardiovascular risk factor. However, it is unclear whether oxidized albumin, which is the most abundant serum protein, induces endothelial damage. The results of this study indicated that with aging processes, the levels of oxidized proteins as well as endothelial microparticles release increased, a novel marker of endothelial damage. Among these, oxidized albumin seems to play a principal role. Through in vitro studies, endothelial cells cultured with oxidized albumin exhibited an increment of endothelial damage markers such as adhesion molecules and apoptosis levels. In addition, albumin oxidation increased the amount of endothelial microparticles that were released. Moreover, endothelial cells with increased oxidative stress undergo senescence. In addition, endothelial cells cultured with oxidized albumin shown a reduction in endothelial cell migration measured by wound healing. As a result, we provide the first evidence that oxidized albumin induces endothelial injury which then contributes to the increase of cardiovascular disease in the elderly subjects.
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Affiliation(s)
- Carlos Luna
- Nephrology Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, Spain
| | - Matilde Alique
- Department of Systems Biology, Physiology Unit, Universidad de Alcalá, Madrid, Spain
| | - Estefanía Navalmoral
- Department of Systems Biology, Physiology Unit, Universidad de Alcalá, Madrid, Spain
| | | | | | - Julia Carracedo
- Nephrology Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, Spain
| | - Rafael Ramírez
- Department of Systems Biology, Physiology Unit, Universidad de Alcalá, Madrid, Spain
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Affiliation(s)
- Anna Uryga
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; ,
| | - Kelly Gray
- Cardiovascular Safety, AstraZeneca, Cambridge CB4 0FZ, United Kingdom;
| | - Martin Bennett
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; ,
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Sun JT, Yang K, Lu L, Zhu ZB, Zhu JZ, Ni JW, Han H, Chen N, Zhang RY. Increased carbamylation level of HDL in end-stage renal disease: carbamylated-HDL attenuated endothelial cell function. Am J Physiol Renal Physiol 2016; 310:F511-7. [PMID: 26764205 DOI: 10.1152/ajprenal.00508.2015] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 12/11/2022] Open
Abstract
It is thought that carbamylated modification plays a crucial role in the development and progression of cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). However, information on the biological effects of carbamylated high-density lipoprotein (C-HDL) in ESRD is poor. The present study investigated the carbamylation level of HDL in ESRD and the effects of C-HDL on endothelial repair properties. HDL was isolated from healthy control subjects (n = 22) and patients with ESRD (n = 30). The carbamylation level of HDL was detected using ELISA. Isolated C-HDL for use in tissue culture experiments was carbamylated in vitro to a similar extent to that observed in ESRD. Human arterial endothelial cells were treated with C-HDL or native HDL to assess their migration, proliferation, and angiogenesis properties. HDL-associated paraoxonase 1 activity was also determined by spectrophotometry assay. Compared with healthy control subjects, the carbamylation level of HDL in ESRD patients was increased and positively correlated with blood urea concentration. In vitro, C-HDL significantly inhibited migration, angiogenesis, and proliferation in endothelial cells. Mechanistic studies revealed that HDL-associated paraoxonase 1 activity was decreased and negatively correlated with the carbamylation level of HDL in ESRD patients. In addition, C-HDL suppressed the expression of VEGF receptor 2 and scavenger receptor class B type I signaling pathways in endothelial cells. In conclusion, the present study identified a significantly increased carbamylation level of HDL in ESRD. Furthermore, C-HDL inhibited endothelial cell repair functions.
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Affiliation(s)
- Jia Teng Sun
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ke Yang
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Cardiovascular Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and
| | - Lin Lu
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng Bin Zhu
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jin Zhou Zhu
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Wei Ni
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Han
- Institute of Cardiovascular Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and
| | - Nan Chen
- Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rui Yan Zhang
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
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Alique M, Luna C, Carracedo J, Ramírez R. LDL biochemical modifications: a link between atherosclerosis and aging. Food Nutr Res 2015; 59:29240. [PMID: 26637360 PMCID: PMC4670441 DOI: 10.3402/fnr.v59.29240] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 11/12/2015] [Accepted: 11/12/2015] [Indexed: 01/17/2023] Open
Abstract
Atherosclerosis is an aging disease in which increasing age is a risk factor. Modified low-density lipoprotein (LDL) is a well-known risk marker for cardiovascular disease. High-plasma LDL concentrations and modifications, such as oxidation, glycosylation, carbamylation and glycoxidation, have been shown to be proatherogenic experimentally in vitro and in vivo. Atherosclerosis results from alterations to LDL in the arterial wall by reactive oxygen species (ROS). Evidence suggests that common risk factors for atherosclerosis raise the likelihood that free ROS are produced from endothelial cells and other cells. Furthermore, oxidative stress is an important factor in the induction of endothelial senescence. Thus, endothelial damage and cellular senescence are well-established markers for atherosclerosis. This review examines LDL modifications and discusses the mechanisms of the pathology of atherosclerosis due to aging, including endothelial damage and oxidative stress, and the link between aging and atherosclerosis.
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Affiliation(s)
- Matilde Alique
- Departamento Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Madrid, Spain;
| | - Carlos Luna
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain
| | - Julia Carracedo
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain
| | - Rafael Ramírez
- Departamento Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Madrid, Spain
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Uryga AK, Bennett MR. Ageing induced vascular smooth muscle cell senescence in atherosclerosis. J Physiol 2015; 594:2115-24. [PMID: 26174609 DOI: 10.1113/jp270923] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 07/08/2015] [Indexed: 12/16/2022] Open
Abstract
Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing include evidence of cell senescence, DNA damage (including telomere attrition), mitochondrial dysfunction, a pro-inflammatory secretory phenotype, defects in proteostasis, epigenetic changes, deregulated nutrient sensing, and exhaustion of progenitor cells. In this model, initial damage to DNA (genomic, telomeric, mitochondrial and epigenetic changes) results in a number of cellular responses (cellular senescence, deregulated nutrient sensing and defects in proteostasis). Ultimately, ongoing damage and attempts at repair by continued proliferation overwhelm reparative capacity, causing loss of specialised cell functions, cell death and inflammation. This review summarises the evidence for accelerated biological ageing in atherosclerosis, the functional consequences of cell ageing on cells comprising the plaque, and the causal role that VSMC senescence plays in atherogenesis.
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Affiliation(s)
- Anna K Uryga
- Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Box 110, Cambridge, CB2 0QQ, UK
| | - Martin R Bennett
- Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Box 110, Cambridge, CB2 0QQ, UK
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