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Chen X, Zhao D, Yu C, Wei J, Zhou G. A novel photosensitive nanoprobe combined with CRISPR/Cas12a for dual signal amplification detection of ANGPTL2. Talanta 2025; 292:128010. [PMID: 40147084 DOI: 10.1016/j.talanta.2025.128010] [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: 02/07/2025] [Revised: 03/20/2025] [Accepted: 03/22/2025] [Indexed: 03/29/2025]
Abstract
The detection of specific protein biomarkers holds significant potential for the early diagnosis of colorectal cancer (CRC). However, the accurate quantification of low-abundance proteins in serum presents a major challenge due to factors such as limited sensitivity and the complexity of the required methodologies. In this work, we established a universal CRISPR/Cas biosensing platform by integrating novel photosensitive nanoprobes (DA/PL@Cu NPs) and CRISPR/Cas12 system (DPC-Cas) for the highly sensitive, specific and user-friendly detection of angiopoietin-like protein 2 (ANGPTL2). The DA/PL@Cu NPs serve as a critical component in the transduction of protein recognition information into nucleic acid amplification events to produce Cas12a activators. The DPC-Cas biosensor integrates DA/PL@Cu NPs-assisted amplification with Cas12a self-amplification, enabling ultrasensitive detection of ANGPTL2 at concentrations as low as 20.00 pg/mL. The proposed DPC-Cas biosensor successfully detected ANGPTL2 in serum, demonstrating significant potential for the early diagnosis of CRC.
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Affiliation(s)
- Xiuyu Chen
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer, Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
| | - Dan Zhao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Changmin Yu
- Key Laboratory of Flexible Electronics (KLOFE) and School of Flexible Electronics (Future Technologies), Nanjing Tech University (Nanjing Tech), Nanjing, 211800, China
| | - Jifu Wei
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer, Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
| | - Guoren Zhou
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer, Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
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Takebayashi K, Suzuki T, Yamauchi M, Hara K, Tsuchiya T, Inukai T, Hashimoto K. Circulating Angiopoietin-like Protein 6 Levels and Clinical Features in Patients with Type 2 Diabetes. Intern Med 2025; 64:643-649. [PMID: 39111892 PMCID: PMC11949676 DOI: 10.2169/internalmedicine.3609-24] [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] [Received: 02/05/2024] [Accepted: 06/16/2024] [Indexed: 03/04/2025] Open
Abstract
Objective The main purpose of this study was to evaluate the associations between circulating angiopoietin-like protein 6 (ANGPTL6) levels and various diabetes- and atherosclerosis-related variables in patients with type 2 diabetes. Methods Serum ANGPTL6 levels in patients with type 2 diabetes hospitalized for glycemic control and/or diabetic education were measured using a chemiluminescent immunoassay. Results Most patients had elevated hemoglobin (Hb) A1c levels; 85.7% and 71.4% of patients had HbA1c levels ≥8%, and ≥9%, respectively. ANGPTL6 levels were significantly higher in patients with type 2 diabetes than in non-diabetic controls. In patients with type 2 diabetes, ANGPTL6 was significantly and positively correlated with the duration of diabetes, systolic blood pressure, gamma-glutamyl transpeptidase, C-reactive protein (CRP), and the intimal medial complex thickness of the carotid artery (IMT), and inversely correlated with HbA1c. In the multiple regression analysis, ANGPTL6 had a significant positive association with triglyceride in one of the models in which it was included as a variable. Furthermore, ANGPTL6 also showed significant positive associations with CRP and IMT in models in which they were included as variables. Conclusion The current study suggests that circulating levels of ANGPTL6 may be negatively associated with poor glycemic control and positively associated with the degree of atherosclerosis, as reflected by IMT, in patients with type 2 diabetes, most of whom had elevated HbA1c levels.
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Affiliation(s)
- Kohzo Takebayashi
- Department of Diabetes, Endocrinology and Hematology, Dokkyo Medical University Saitama Medical Center, Japan
| | - Tatsuhiko Suzuki
- Department of Emergency and Critical Care Medicine, Emergency and Critical Care Center, Dokkyo Medical University Saitama Medical Center, Japan
| | - Mototaka Yamauchi
- Department of Diabetes, Endocrinology and Hematology, Dokkyo Medical University Saitama Medical Center, Japan
| | - Kenji Hara
- Department of Diabetes, Endocrinology and Hematology, Dokkyo Medical University Saitama Medical Center, Japan
| | - Takafumi Tsuchiya
- Department of Diabetes, Endocrinology and Hematology, Dokkyo Medical University Saitama Medical Center, Japan
| | | | - Koshi Hashimoto
- Department of Diabetes, Endocrinology and Hematology, Dokkyo Medical University Saitama Medical Center, Japan
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Hiramoto K, Kubo S, Tsuji K, Sugiyama D, Hamano H. Decreased Memory and Learning Ability Mediated by Bmal1/M1 Macrophages/Angptl2/Inflammatory Cytokine Pathway in Mice Exposed to Long-Term Blue Light Irradiation. Curr Issues Mol Biol 2024; 46:4924-4934. [PMID: 38785563 PMCID: PMC11120424 DOI: 10.3390/cimb46050295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/16/2024] [Accepted: 05/16/2024] [Indexed: 05/25/2024] Open
Abstract
Humans are persistently exposed to massive amounts of blue light via sunlight, computers, smartphones, and similar devices. Although the positive and negative effects of blue light on living organisms have been reported, its impact on learning and memory remains unknown. Herein, we examined the effects of widespread blue light exposure on the learning and memory abilities of blue light-exposed mice. Ten-week-old male ICR mice were divided into five groups (five mice/group) and irradiated with blue light from a light-emitting diode daily for 6 months. After 6 months of blue light irradiation, mice exhibited a decline in memory and learning abilities, assessed using the Morris water maze and step-through passive avoidance paradigms. Blue light-irradiated mice exhibited a decreased expression of the clock gene brain and muscle arnt-like 1 (Bmal1). The number of microglia and levels of M1 macrophage CC-chemokine receptor 7 and inducible nitric oxide synthase were increased, accompanied by a decrease in M2 macrophage arginase-1 levels. Levels of angiopoietin-like protein 2 and inflammatory cytokines interleukin-6, tumor necrosis factor-α, and interleukin-1β were elevated. Our findings suggest that long-term blue light exposure could reduce Bmal1 expression, activate the M1 macrophage/Angptl2/inflammatory cytokine pathway, induce neurodegeneration, and lead to a decline in memory.
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Affiliation(s)
- Keiichi Hiramoto
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka 513-8670, Mie, Japan
| | - Sayaka Kubo
- Research Department, Daiichi Sankyo Healthcare Co., Ltd., Chuo-ku 140-8170, Tokyo, Japan; (S.K.); (K.T.); (D.S.); (H.H.)
| | - Keiko Tsuji
- Research Department, Daiichi Sankyo Healthcare Co., Ltd., Chuo-ku 140-8170, Tokyo, Japan; (S.K.); (K.T.); (D.S.); (H.H.)
| | - Daijiro Sugiyama
- Research Department, Daiichi Sankyo Healthcare Co., Ltd., Chuo-ku 140-8170, Tokyo, Japan; (S.K.); (K.T.); (D.S.); (H.H.)
| | - Hideo Hamano
- Research Department, Daiichi Sankyo Healthcare Co., Ltd., Chuo-ku 140-8170, Tokyo, Japan; (S.K.); (K.T.); (D.S.); (H.H.)
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Hammad MM, Channanath AM, Abu-Farha M, Rahman A, Al Khairi I, Cherian P, Alramah T, Alam-Eldin N, Al-Mulla F, Thanaraj TA, Abubaker J. Adolescent obesity and ANGPTL8: correlations with high sensitivity C-reactive protein, leptin, and chemerin. Front Endocrinol (Lausanne) 2023; 14:1314211. [PMID: 38189043 PMCID: PMC10766807 DOI: 10.3389/fendo.2023.1314211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/06/2023] [Indexed: 01/09/2024] Open
Abstract
Angiopoietin-like proteins (ANGPTLs) mediate many metabolic functions. We had recently reported increased plasma levels of ANGPTL8 in obese adults of Arab ethnicity. However, data on ANGPTL8 levels in adolescent obesity is lacking. Arab population is characterized by a rapid transition, due to sudden wealth seen in the post-oil era, in lifestyle, food habits and extent of physical activity. We adopted a cross-sectional study on Arab adolescents from Kuwait to examine the role of ANGPTL8 in adolescent obesity. The study cohort included 452 adolescents, aged 11-14 years, recruited from Middle Schools across Kuwait. BMI-for-age growth charts were used to categorize adolescents as normal-weight, overweight, and obese. ELISA and bead-based multiplexing assays were used to measure plasma levels of ANGPTL8 and other inflammation and obesity-related biomarkers. Data analysis showed significant differences in the plasma levels of ANGPTL8 among the three subgroups, with a significant increase in overweight and obese children compared to normal-weight children. This observation persisted even when the analysis was stratified by sex. Multinomial logistic regression analysis illustrated that adolescents with higher levels of ANGPTL8 were 7 times more likely to become obese and twice as likely to be overweight. ANGPTL8 levels were correlated with those of hsCRP, leptin and chemerin. ANGPTL8 level had a reasonable prognostic power for obesity with an AUC of 0.703 (95%-CI=0.648-0.759). These observations relating to increased ANGPTL8 levels corresponding to increased BMI-for-age z-scores indicate that ANGPTL8, along with hsCRP, leptin and chemerin, could play a role in the early stages of obesity development in children. ANGPTL8 is a potential early marker for adolescent obesity and is associated with well-known obesity and inflammatory markers.
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Affiliation(s)
- Maha M. Hammad
- Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Arshad M. Channanath
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Mohamed Abu-Farha
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Abdur Rahman
- Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Kuwait City, Kuwait
| | - Irina Al Khairi
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Preethi Cherian
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Tahani Alramah
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Nada Alam-Eldin
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Fahd Al-Mulla
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | | | - Jehad Abubaker
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
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Thorin E, Labbé P, Lambert M, Mury P, Dagher O, Miquel G, Thorin-Trescases N. Angiopoietin-Like Proteins: Cardiovascular Biology and Therapeutic Targeting for the Prevention of Cardiovascular Diseases. Can J Cardiol 2023; 39:1736-1756. [PMID: 37295611 DOI: 10.1016/j.cjca.2023.06.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/27/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023] Open
Abstract
Despite the best pharmacologic tools available, cardiovascular diseases (CVDs) remain a major cause of morbidity and mortality in developed countries. After 2 decades of research, new therapeutic targets, such as angiopoietin-like proteins (ANGPTLs), are emerging. ANGPTLs belong to a family of 8 members, from ANGPTL1 to ANGPTL8; they have structural homology with angiopoietins and are secreted in the circulation. ANGPTLs display a multitude of physiological and pathologic functions; they contribute to inflammation, angiogenesis, cell death, senescence, hematopoiesis, and play a role in repair, maintenance, and tissue homeostasis. ANGPTLs-particularly the triad ANGPTL3, 4, and 8-have an established role in lipid metabolism through the regulation of triacylglycerol trafficking according to the nutritional status. Some ANGPTLs also contribute to glucose metabolism. Therefore, dysregulation in ANGPTL expression associated with abnormal circulating levels are linked to a plethora of CVD and metabolic disorders including atherosclerosis, heart diseases, diabetes, but also obesity and cancers. Because ANGPTLs bind to different receptors according to the cell type, antagonists are therapeutically inadequate. Recently, direct inhibitors of ANGPTLs, mainly ANGPTL3, have been developed, and specific monoclonal antibodies and antisense oligonucleotides are currently being tested in clinical trials. The aim of the current review is to provide an up-to-date preclinical and clinical overview on the function of the 8 members of the ANGPTL family in the cardiovascular system, their contribution to CVD, and the therapeutic potential of manipulating some of them.
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Affiliation(s)
- Eric Thorin
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Québec, Canada.
| | - Pauline Labbé
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada
| | - Mélanie Lambert
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada
| | - Pauline Mury
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada
| | - Olina Dagher
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Québec, Canada; Department of Cardiac Sciences, Libin Cardiovascular Institute, Calgary, Alberta, Canada
| | - Géraldine Miquel
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada
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Hernández JL, Ocejo-Vinyals JG, Renuncio-García M, González-López E, Blanco R, González-López MA. Angiopoietin-like 2 Protein and Hidradenitis Suppurativa: A New Biomarker for Disease Severity. Biomedicines 2023; 11:biomedicines11041204. [PMID: 37189824 DOI: 10.3390/biomedicines11041204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 05/17/2023] Open
Abstract
Hidradenitis suppurativa (HS) is a chronic inflammatory disease whose pathogenesis is not fully understood at present. The role of proinflammatory cytokines, several adipokines, retinol-binding protein 4, angiopoietin-2 and other molecules has been previously reported. Angiopoietin-like 2 protein (ANGPTL2) is a glycoprotein belonging to the angiopoietin-like family that may play a pivotal role in the pathogenesis of several chronic inflammatory diseases. To our knowledge, the role of serum ANGPTL2 levels in HS has not been assessed to date. In the current case-control study, we aimed to investigate serum ANGPTL2 levels in HS patients and controls and to assess whether ANGPTL2 levels could be associated with the severity of HS. Ninety-four patients with HS and sixty controls of similar age and sex were included in the study. Demographic, anthropometric, and clinical data, as well as routine laboratory parameters and serum concentrations of ANGPTL2, were assessed in all participants. HS patients had significantly higher serum ANGPTL2 levels than controls after adjusting for confounders. Moreover, ANGPTL2 concentrations positively correlated with disease duration and severity. Our results indicate for the first time that serum ANGPTL2 concentrations are elevated in HS patients compared to controls and correlate with the duration of the disease. Besides, ANGPTL2 might serve as a biomarker of HS severity.
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Affiliation(s)
- José L Hernández
- Internal Medicine Division, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain
- Medicine and Psychiatry Department, Universidad de Cantabria, 39011 Santander, Spain
- Valdecilla Research Institute, Valdecilla (IDIVAL), 39011 Santander, Spain
| | - J Gonzalo Ocejo-Vinyals
- Valdecilla Research Institute, Valdecilla (IDIVAL), 39011 Santander, Spain
- Immunology Division, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain
| | - Mónica Renuncio-García
- Immunology Division, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain
| | - Elena González-López
- Immunology Division, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain
| | - Ricardo Blanco
- Medicine and Psychiatry Department, Universidad de Cantabria, 39011 Santander, Spain
- Valdecilla Research Institute, Valdecilla (IDIVAL), 39011 Santander, Spain
- Rheumatology Division, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain
| | - Marcos A González-López
- Medicine and Psychiatry Department, Universidad de Cantabria, 39011 Santander, Spain
- Valdecilla Research Institute, Valdecilla (IDIVAL), 39011 Santander, Spain
- Dermatology Division, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain
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Han F, Wang C, Cheng P, Liu T, Wang WS. Bone marrow mesenchymal stem cells derived exosomal miRNAs can modulate diabetic bone-fat imbalance. Front Endocrinol (Lausanne) 2023; 14:1149168. [PMID: 37124755 PMCID: PMC10145165 DOI: 10.3389/fendo.2023.1149168] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 03/09/2023] [Indexed: 05/02/2023] Open
Abstract
Background Diabetes mellitus is a chronic metabolic disease with systemic complications. Patient with diabetes have increased risks of bone fracture. Previous studies report that diabetes could affect bone metabolism, however, the underlying mechanism is still unclear. Methods We isolated exosomes secreted by bone marrow mesenchymal stem cells of normal and diabetic mice and test their effects on osteogenesis and adipogenesis. Then we screened the differential microRNAs by high-throughput sequencing and explored the function of key microRNA in vitro and in vivo. Results We find that lower bone mass and higher marrow fat accumulation, also called bone-fat imbalance, exists in diabetic mouse model. Exosomes secreted by normal bone marrow mesenchymal stem cells (BMSCs-Exos) enhanced osteogenesis and suppressed adipogenesis, while these effects were diminished in diabetic BMSCs-Exos. miR-221, as one of the highly expressed miRNAs within diabetic BMSCs-Exos, showed abilities of suppressing osteogenesis and promoting adipogenesis both in vitro and in vivo. Elevation of miR-221 level in normal BMSCs-Exos impairs the ability of regulating osteogenesis and adipogenesis. Intriguingly, using the aptamer delivery system, delivery normal BMSCs-Exos specifically to BMSCs increased bone mass, reduced marrow fat accumulation, and promoted bone regeneration in diabetic mice. Conclusion We demonstrate that BMSCs derived exosomal miR-221 is a key regulator of diabetic osteoporosis, which may represent a potential therapeutic target for diabetes-related skeletal disorders.
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Affiliation(s)
- Fei Han
- Medical College, Shihezi University, Shihezi, Xinjiang, China
- Department of Orthopaedics, The First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, China
| | - Chao Wang
- Medical College, Shihezi University, Shihezi, Xinjiang, China
- Department of Orthopaedics, The First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, China
| | - Peng Cheng
- Division of Geriatric Endocrinology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China
- *Correspondence: Peng Cheng, ; Ting Liu, ; Wei-Shan Wang,
| | - Ting Liu
- Department of Endocrinology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, China
- *Correspondence: Peng Cheng, ; Ting Liu, ; Wei-Shan Wang,
| | - Wei-Shan Wang
- Medical College, Shihezi University, Shihezi, Xinjiang, China
- Department of Orthopaedics, The First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, China
- *Correspondence: Peng Cheng, ; Ting Liu, ; Wei-Shan Wang,
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Zhong Z, Zhang H, Xu T, Hao J, Chen X, Sun S, Yang J, Sun J, Lin H, Guo H. Identification and verification of immune-related biomarkers and immune infiltration in diabetic heart failure. Front Cardiovasc Med 2022; 9:931066. [PMID: 36465455 PMCID: PMC9712450 DOI: 10.3389/fcvm.2022.931066] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 10/31/2022] [Indexed: 10/25/2023] Open
Abstract
PURPOSE Diabetic heart failure (DHF) or cardiomyopathy is a common complication of diabetes; however, the underlying mechanism is not clear. In the present study, the authors searched for differentially expressed genes associated with DHF and the molecular types of immune cells based on bioinformatics. METHODS The RNA expression dataset of DHF was obtained from the NCBI Gene Expression Omnibus (GEO) database. After preprocessing the data, the differentially expressed genes (DEGs) between the DHF group and the non-diabetic heart failure (NHF) group were screened and intersected with immune-related genes (IRGs) in the ImmPort database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID tool. The ssGSEA algorithm was used to evaluate immune infiltration of the heart tissue in each group. In addition, the protein-protein interaction (PPI) network and miRNA-mRNA network were constructed using the STRING online website and Cytoscape program. Finally, validation analysis was performed using animal models. RESULTS Eight immune-related core genes were identified. GO and KEGG showed that core genes were mainly enriched in angiogenesis and cytokine-cytokine receptor interaction. Immune infiltration results showed that activated dendritic cells, central memory CD4 T cells, central memory CD8 T cells, myeloid-derived suppressor cells (MDSCs), neutrophils, and regulatory T cells may be involved in DHF. Neutrophils may play a key role in the pathogenesis of HF in diabetes. CONCLUSION Immune-related core genes and immune infiltrating cells provide a new perspective on the pathogenesis of DHF.
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Affiliation(s)
- Zuoquan Zhong
- Department of Cardiology, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang, China
| | - Hanlin Zhang
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ting Xu
- Department of Cardiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jinjin Hao
- Department of Cardiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xing Chen
- Department of Respiratory Medicine, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang, China
| | - Shimin Sun
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jinjin Yang
- Department of Cardiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jing Sun
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hui Lin
- Department of Cardiovascular, Lihuili Hospital Affiliated to Ningbo University, Ningbo, Zhejiang, China
| | - Hangyuan Guo
- Department of Cardiology, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang, China
- College of Medicine, Shaoxing University, Shaoxing, Zhejiang, China
- Shaoxing People’s Hospital, Shaoxing Key Laboratory of Cardio-Cerebral Vascular Disease Rehabilitation Technology Research, Shaoxing, Zhejiang, China
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Zhao W, Morinaga J, Ukawa S, Endo M, Yamada H, Kawamura T, Wakai K, Tsushita K, Ando M, Suzuki K, Oike Y, Tamakoshi A. Plasma angiopoietin-like protein 2 levels and mortality risk among younger-old Japanese people: a population-based case-cohort study. J Gerontol A Biol Sci Med Sci 2022; 77:1150-1158. [PMID: 35037044 DOI: 10.1093/gerona/glac017] [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: 07/12/2021] [Indexed: 11/14/2022] Open
Abstract
Aging is important medical and social problem. Excessive angiopoietin-like protein (ANGPTL)-2 signaling causes chronic tissue inflammation, promoting development and progression of aging-related diseases. Moreover, circulating ANGPTL2 levels reportedly predict risk of some aging-related diseases and subsequent death. However, there are as yet no reports of whether circulating ANGPTL2 levels predict vital prognosis in younger-old, community-dwelling populations. This study investigated associations between plasma ANGPTL2 levels and all-cause and specific-cause mortality in this population. The case-cohort study was abstracted from an on-going, age-specific prospective cohort study: the New Integrated Suburban Seniority Investigation Project. This project enrolled 3073 participants aged 64 years at the beginning of the investigation from 1996 through 2005. A sub-cohort of 714 randomly sampled participants plus 387 cases representing deceased participants followed through 2015 underwent survival analysis. Plasma ANGPTL2 concentrations were positively associated with >80% and 100% higher risk of all-cause mortality and cancer mortality, respectively, after adjustment for gender, smoking, alcohol consumption, walking time, sleep duration, caloric intake, medical status, disease history, BMI, and triglyceride, creatinine, uric acid, and high sensitivity C-reactive protein levels. More robust association between ANGPTL2 levels and all-cause and cancer mortality was seen in subjects with either frailties or with lifestyles of heavier drinking or current smoking. Elevated plasma ANGPTL2 levels are associated with high all-cause and cancer mortality in a community-dwelling sample of younger-old adults. These findings expand our knowledge of human aging and associated diseases.
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Affiliation(s)
- Wenjing Zhao
- School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, China.,Department of Public Health, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Jun Morinaga
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shigekazu Ukawa
- Research Unit of Advanced Interdisciplinary Care Science, Graduate School of Human Life Science, Osaka City University, Osaka, Japan
| | - Motoyoshi Endo
- Department of Molecular Biology, University of Occupational and Environmental Health, Japan
| | - Hiroya Yamada
- Department of Hygiene, Fujita Health University School of Medicine, Aichi, Japan
| | | | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Kazuyo Tsushita
- Comprehensive Health Science Center, Aichi Health Promotion Public Interest Foundation, Chita, Aichi, Japan
| | - Masahiko Ando
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Koji Suzuki
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Aichi, Japan
| | - Yuichi Oike
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Akiko Tamakoshi
- Department of Public Health, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
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Thorin-Trescases N, Labbé P, Mury P, Lambert M, Thorin E. Angptl2 is a Marker of Cellular Senescence: The Physiological and Pathophysiological Impact of Angptl2-Related Senescence. Int J Mol Sci 2021; 22:12232. [PMID: 34830112 PMCID: PMC8624568 DOI: 10.3390/ijms222212232] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/04/2021] [Accepted: 11/09/2021] [Indexed: 02/07/2023] Open
Abstract
Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases.
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Affiliation(s)
- Nathalie Thorin-Trescases
- Montreal Heart Institute, University of Montreal, Montreal, QC H1T 1C8, Canada; (P.L.); (P.M.); (M.L.); (E.T.)
| | - Pauline Labbé
- Montreal Heart Institute, University of Montreal, Montreal, QC H1T 1C8, Canada; (P.L.); (P.M.); (M.L.); (E.T.)
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Pauline Mury
- Montreal Heart Institute, University of Montreal, Montreal, QC H1T 1C8, Canada; (P.L.); (P.M.); (M.L.); (E.T.)
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Mélanie Lambert
- Montreal Heart Institute, University of Montreal, Montreal, QC H1T 1C8, Canada; (P.L.); (P.M.); (M.L.); (E.T.)
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Eric Thorin
- Montreal Heart Institute, University of Montreal, Montreal, QC H1T 1C8, Canada; (P.L.); (P.M.); (M.L.); (E.T.)
- Department of Surgery, Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
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Influence of Angptl1 on osteoclast formation and osteoblastic phenotype in mouse cells. BMC Musculoskelet Disord 2021; 22:398. [PMID: 33910546 PMCID: PMC8082671 DOI: 10.1186/s12891-021-04278-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 04/15/2021] [Indexed: 01/19/2023] Open
Abstract
Background Osteoblasts and osteoclasts play important roles during the bone remodeling in the physiological and pathophysiological states. Although angiopoietin family Angiopoietin like proteins (Angptls), including Angptl1, have been reported to be involved in inflammation, lipid metabolism and angiogenesis, the roles of Angptl1 in bone have not been reported so far. Methods We examined the effects of Angptl1 on the osteoblast and osteoclast phenotypes using mouse cells. Results Angptl1 significantly inhibited the osteoclast formation and mRNA levels of tartrate-resistant acid phosphatase and cathepsin K enhanced by receptor activator of nuclear factor κB ligand in RAW 264.7 and mouse bone marrow cells. Moreover, Angptl1 overexpression significantly enhanced Osterix mRNA levels, alkaline phosphatase activity and mineralization induced by bone morphogenetic protein-2 in ST2 cells, although it did not affect the expression of osteogenic genes in MC3T3-E1 and mouse osteoblasts. On the other hand, Angptl1 overexpression significantly reduced the mRNA levels of peroxisome proliferator-activated receptor γ and adipocyte protein-2 as well as the lipid droplet formation induced by adipogenic medium in 3T3-L1 cells. Conclusions The present study first indicated that Angptl1 suppresses and enhances osteoclast formation and osteoblastic differentiation in mouse cells, respectively, although it inhibits adipogenic differentiation of 3T3-L1 cells. These data suggest the possibility that Angptl1 might be physiologically related to bone remodeling.
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12
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Seyhanli Z, Seyhanli A, Aksun S, Pamuk BO. Evaluation of serum Angiopoietin-like protein 2 (ANGPTL-2), Angiopoietin-like protein 8 (ANGPTL-8), and high-sensitivity C-reactive protein (hs-CRP) levels in patients with gestational diabetes mellitus and normoglycemic pregnant women. J Matern Fetal Neonatal Med 2021; 35:5647-5652. [PMID: 33615956 DOI: 10.1080/14767058.2021.1888919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE In the present study, we aimed to investigate the role of the fasting serum levels of Anjiopoetın 2 - like protein (ANGPTL2), Anjiopoetın 8-like protein (ANGPTL8), and high-sensitivity C-reactive protein (hs-CRP) in the etiopathogenesis of gestational diabetes mellitus (GDM), and analyze the relationships between insulin resistance parameters. MATERIAL AND METHOD The 90 individuals admitted to İzmir Katip Celebi University Hospital Internal Medicine, Endocrinology and Obstetrics, and gynecology outpatient clinic were included in the study of similar ages and similar demographic characteristics. Forty-five women with diet-controlled GDM and 45 women with normoglycemic pregnancy were enrolled. ANGPTL-2, ANGPTL-8, hs-CRP, creatinine, ALT, GGT, lipid profile, HBA1c(%), and serum insülin, c-peptide levels were studied in the fasting serum samples of research groups. All individuals had 75-g OGTT testing. GDM screening was performed at 24-28 weeks' gestation. Exclusion criteria were as follows: Age <18 years or >40 years, pregestational diabetes (type 1 or 2), drug or alcohol abuse, thyroid dysfunction, Hepatitis B, and other infectious diseases (Herpes virus, Streptococcus B carriers, Chlamydia and Candida), Thalassemia carriers or other significant medical conditions, the use of any medication that interferes with lipid or glucose metabolism that would affect glucose regulation. RESULT Forty-five women with GDM and for the control group, 45 women with normoglycemic pregnant women were identified. The mean gestational age was 30.7 (18-38) for GDM and 29.6 (24-39) for the control group. Serum ANGPTL-8 (GDM =19.5 ± 93 Control = 0.73 ± 3.78 p = <.001). There was a statistically significant difference between the case and control groups for serum ANGPTL-8 levels. Serum ANGPTL-2 (GDM =19.9 ± 23.1 Control = 26.0 ± 23.4 p = .105) and serum hs-CRP(GDM =106 ± 65.1 Control =98.2 ± 87.3 p = .768). There was no statistically significant difference between the case and control groups for serum ANGPTL-2 and hsCRP levels. Serum ANGPTL8 levels were positively correlated with FPG (r = 0.391, p = <.001), FPI (r = 0.212, p = .045), 1-h PPG (r = 0.514, p = <.001), 2-h PPG (r = 0.502, p = <.001), HOMA-IR) score (r = 0.310, p = .003), TG (r = 0.245, p = .020); they were not except for BMI, hs-CRP levels and ANGPTL2 levels. CONCLUSIONS ANGPTL8 levels were significantly higher in GDM than in healthy control group. ANGPTL2 levels and hs-CRP levels were similar to the healthy control group. Elevated serum ANGPTL8 levels were correlated significantly with insulin resistance parameters, the main component of GDM pathophysiology. Our data showed that ANGPTL8 could be a new biomarker for diagnosing GDM.
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Affiliation(s)
- Zeynep Seyhanli
- Obstetrics and Gynaecology, Izmir Gaziemir Nevvar Salih Isgoren State Hospital, Izmir, Turkey
| | - Ahmet Seyhanli
- Department of Internal Medicine (Hematology), Sivas Numune Hastanesi, Sivas, Turkey
| | - Saliha Aksun
- Biochemistry Department, Izmir Katip Celebi University Atatürk Training and Research Hospital, Izmir, Turkey
| | - Baris Onder Pamuk
- Endocrine and Metabolic Diseases Department Izmir, Izmir Katip Celebi University, Atatürk Training and Research Hospital, Izmir, Turkey
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Yin R, Zhang N, Zhang D, Zhao W, Ke J, Zhao D. Higher levels of circulating ANGPTL2 are associated with macular edema in patients with type 2 diabetes. Medicine (Baltimore) 2021; 100:e24638. [PMID: 33578584 PMCID: PMC7886454 DOI: 10.1097/md.0000000000024638] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 01/15/2021] [Indexed: 01/05/2023] Open
Abstract
Macular edema (ME) is an inflammatory disease characterized by increased microvascular permeability. Here, we proposed that plasma angiopoietin-like protein 2 (ANGPTL2) level may be related to the severity of ME patients with type 2 diabetes mellitus (T2DM). In this cross-sectional study, 172 T2DM patients were recruited and divided into clinically significant macular edema (CSME), non-CSME (nCSME), and control groups. Serum ANGPTL2 level was quantified by ELISA and best corrected vision acuity (BCVA) was detected. After adjust age, sex, body mass index (BMI), and duration of diabetes variables, ANGPTL2 performed statistics difference among CSME-, nCSME-groups, and control group (4.46 [3.97, 4.96, 95%CI] ng/mL in CSME group, 3.80 [3.42, 4.18, 95%CI] ng/mL in nCSME-group, 3.33 [3.03, 3.63, 95%CI] ng/mL in control, P < .01). After adjustment of confounding factors, high levels of circulating ANGPTL2 were related with the diagnosis of ME, BCVA, and C reactive protein (CRP) through univariate regression analysis (P < .05). Meanwhile, in the multiple regression model, ANGPTL2 took the mainly effect proportion for the diagnosis of diabetic macular edema (DME), with a LogWorth value 3.559 (P < .001). Our study suggested that elevated circulating ANGPTL2 may be associated with the development of DME and the severity of visual impairment in patients with type 2 diabetes.
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Affiliation(s)
- Ruili Yin
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University
- Beijing Key Laboratory of Diabetes Research and Care
| | - Ning Zhang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University
- Beijing Key Laboratory of Diabetes Research and Care
| | - Dawei Zhang
- Department of Ophthalmology, Beijing Luhe Hospital Capital Medical University, Beijing, 101149, China
| | - Wenying Zhao
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University
| | - Jing Ke
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University
| | - Dong Zhao
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University
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14
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Wang Y, Zheng Z, Yang Y, Lang J, Zhang N, Yang L, Zhao D. Angiopoietin-like 2 is a potential biomarker for diabetic foot patients. BMC Endocr Disord 2020; 20:178. [PMID: 33256685 PMCID: PMC7706189 DOI: 10.1186/s12902-020-00657-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 11/22/2020] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Circulating angiopoietin-like 2 (ANGPTL2) protein levels are known to be significantly increased in numerous chronic inflammatory diseases and are associated with the diagnosis and/or prognosis of cardiovascular diseases, diabetes, chronic kidney disease, and various types of cancers. However, no data regarding the relationship between ANGPTL2 and diabetic foot ulcers (DFUs) are available. Here, we explored the potential link between ANGPTL2 and DFUs. METHODS A total of 68 participants with type 2 diabetes mellitus (T2DM) were recruited, including 28 patients with DFU and 40 diabetic patients without DFUs. The clinical characteristics of T2DM patients with and without DFUs were compared. Serum concentrations of ANGPTL2 and VEGF were measured using enzyme-linked immunosorbent assay (ELISA) kits. The correlations between ANGPTL2 and clinical variables were analyzed. Multiple linear regression and logistic regression models were constructed to test the associations between ANGPTL2 and the severity and presence of DFUs. RESULTS Serum levels of ANGPTL2 were higher in patients with DFUs than those in diabetic controls. Serum ANGPTL2 levels were higher in the advanced stages of DFUs. Spearman correlation analysis revealed strong positive associations of ANGPTL2 with CRP, VEGF and ESR in all subjects. In addition, serum ANGPTL2 was still positively correlated with DFUs stage after adjusting the risk factors. After adjusting for age, sex, HbA1C and duration of diabetes, ANGPTL2 was found to be independently associated with the presence of DFUs. CONCLUSIONS Circulating ANGPTL2 levels are an independent risk factor for DFUs. This suggests that ANGPTL2 may play important roles in the development of DFUs, a possibility that needs to investigated in prospective studies.
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Affiliation(s)
- Yan Wang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149 China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149 China
| | - Zhaohui Zheng
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149 China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149 China
| | - Yuxian Yang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149 China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149 China
| | - Jianan Lang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149 China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149 China
| | - Ning Zhang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149 China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149 China
| | - Longyan Yang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149 China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149 China
| | - Dong Zhao
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149 China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149 China
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Morinaga J, Kakuma T, Fukami H, Hayata M, Uchimura K, Mizumoto T, Kakizoe Y, Miyoshi T, Shiraishi N, Adachi M, Izumi Y, Kuwabara T, Okadome Y, Sato M, Horiguchi H, Sugizaki T, Kadomatsu T, Miyata K, Tajiri S, Tajiri T, Tomita K, Kitamura K, Oike Y, Mukoyama M. Circulating angiopoietin-like protein 2 levels and mortality risk in patients receiving maintenance hemodialysis: a prospective cohort study. Nephrol Dial Transplant 2020; 35:854-860. [PMID: 31840173 DOI: 10.1093/ndt/gfz236] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 10/10/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Patients undergoing hemodialysis treatment have a poor prognosis, as many develop premature aging. Systemic inflammatory conditions often underlie premature aging phenotypes in uremic patients. We investigated whether angiopoietin-like protein 2 (ANGPTL 2), a factor that accelerates the progression of aging-related and noninfectious inflammatory diseases, was associated with increased mortality risk in hemodialysis patients. METHODS We conducted a multicenter prospective cohort study of 412 patients receiving maintenance hemodialysis and evaluated the relationship between circulating ANGPTL2 levels and the risk for all-cause mortality. Circulating ANGPTL2 levels were log-transformed to correct for skewed distribution and analyzed as a continuous variable. RESULTS Of 412 patients, 395 were included for statistical analysis. Time-to-event data analysis showed high circulating ANGPTL2 levels were associated with an increased risk for all-cause mortality after adjustment for age, sex, hemodialysis vintage, nutritional status, metabolic parameters and circulating high-sensitivity C-reactive protein levels {hazard ratio [HR] 2.04 [95% confidence interval (CI) 1.10-3.77]}. High circulating ANGPTL2 levels were also strongly associated with an increased mortality risk, particularly in patients with a relatively benign prognostic profile [HR 3.06 (95% CI 1.86-5.03)]. Furthermore, the relationship between circulating ANGPTL2 levels and mortality risk was particularly strong in patients showing few aging-related phenotypes, such as younger patients [HR 7.99 (95% CI 3.55-18.01)], patients with a short hemodialysis vintage [HR 3.99 (95% CI 2.85-5.58)] and nondiabetic patients [HR 5.15 (95% CI 3.19-8.32)]. CONCLUSION We conclude that circulating ANGPTL2 levels are positively associated with mortality risk in patients receiving maintenance hemodialysis and that ANGPTL2 could be a unique marker for the progression of premature aging and subsequent mortality risk in uremic patients, except those with significant aging-related phenotypes.
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Affiliation(s)
- Jun Morinaga
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.,Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.,Department of Clinical Investigation, Kumamoto University Hospital, Kumamoto, Japan.,Biostatistics Center, Kurume University, Fukuoka, Japan
| | | | - Hirotaka Fukami
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.,Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Manabu Hayata
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kohei Uchimura
- Third Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Teruhiko Mizumoto
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yutaka Kakizoe
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Taku Miyoshi
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Naoki Shiraishi
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masataka Adachi
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuichiro Izumi
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takashige Kuwabara
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yusuke Okadome
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Michio Sato
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Haruki Horiguchi
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Taichi Sugizaki
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Tsuyoshi Kadomatsu
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Keishi Miyata
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | | | | | - Kimio Tomita
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kenichiro Kitamura
- Third Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yuichi Oike
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masashi Mukoyama
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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Fukami H, Morinaga J, Okadome Y, Nishiguchi Y, Iwata Y, Kanki T, Nakagawa T, Izumi Y, Kakizoe Y, Kuwabara T, Horiguchi H, Sato M, Kadomatsu T, Miyata K, Tajiri T, Oike Y, Mukoyama M. Circulating angiopoietin-like protein 2 levels and arterial stiffness in patients receiving maintenance hemodialysis: A cross-sectional study. Atherosclerosis 2020; 315:18-23. [PMID: 33197687 DOI: 10.1016/j.atherosclerosis.2020.10.890] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 10/06/2020] [Accepted: 10/28/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Chronic low-grade inflammation is receiving much attention as a critical pathology that induces various aging phenotypes, a concept known as "inflammaging". Uremic patients undergoing hemodialysis therapy show vascular aging phenotypes characterized by greater arterial stiffness and calcification compared to healthy controls of the same generation. In the current study, we investigated whether levels of inflammaging markers in the circulation were associated with vascular aging phenotypes in hemodialysis patients, as estimated by the cardio-ankle vascular index (CAVI). METHODS We conducted a multicenter cross-sectional study of 412 patients receiving hemodialysis and evaluated the relationship between circulating hs-CRP or ANGPTL2 levels, as markers of inflammaging, and CAVI. RESULTS Of 412 patients, 376 were analyzed statistically. While circulating hs-CRP levels had no significant association with CAVI, generalized linear models revealed that high circulating ANGPTL2 levels were significantly associated with increasing CAVI after adjustment for classical metabolic factors and hemodialysis-related parameters [β 0.63 (95%CI 0.07-1.18)]. Exploratory analysis revealed that high circulating ANGPTL2 levels were also strongly associated with increased CAVI, particularly in patients with conditions of increased vascular mechanical stress, such elevated blood pressure [β 1.00 (95%CI 0.23-1.76)], elevated pulse pressure [β 0.75 (95%CI 0.52-0.98)], or excess body fluid [β 1.25 (95%CI 0.65-1.84)]. CONCLUSIONS We conclude that circulating levels of ANGPTL2 rather than hs-CRP are positively associated with CAVI in the uremic population and that ANGPTL2 could be a unique marker of progression of vascular aging in patients receiving hemodialysis.
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Affiliation(s)
- Hirotaka Fukami
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan; Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Jun Morinaga
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan; Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan; Department of Clinical Investigation, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.
| | - Yusuke Okadome
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Yoshihiko Nishiguchi
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Yasunobu Iwata
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Tomoko Kanki
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Terumasa Nakagawa
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Yuichiro Izumi
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Yutaka Kakizoe
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Takashige Kuwabara
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Haruki Horiguchi
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Michio Sato
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Tsuyoshi Kadomatsu
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Keishi Miyata
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan
| | - Tetsuya Tajiri
- Medical Corporation, Jinseikai, 2-3-10 Toshima-nishi Higashi-ku, Kumamoto, Kumamoto, 861-8043, Japan
| | - Yuichi Oike
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.
| | - Masashi Mukoyama
- Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto, 860-8556, Japan.
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Chia PY, Teo A, Yeo TW. Overview of the Assessment of Endothelial Function in Humans. Front Med (Lausanne) 2020; 7:542567. [PMID: 33117828 PMCID: PMC7575777 DOI: 10.3389/fmed.2020.542567] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 08/27/2020] [Indexed: 12/26/2022] Open
Abstract
The endothelium is recognized to play an important role in various physiological functions including vascular tone, permeability, anticoagulation, and angiogenesis. Endothelial dysfunction is increasingly recognized to contribute to pathophysiology of many disease states, and depending on the disease stimuli, mechanisms underlying the endothelial dysfunction may be markedly different. As such, numerous techniques to measure different aspects of endothelial dysfunction have been developed and refined as available technology improves. Current available reviews on quantifying endothelial dysfunction generally concentrate on a single aspect of endothelial function, although diseases may affect more than one aspect of endothelial function. Here, we aim to provide an overview on the techniques available for the assessment of the different aspects of endothelial function in humans, human tissues or cells, namely vascular tone modulation, permeability, anticoagulation and fibrinolysis, and the use of endothelial biomarkers as predictors of outcomes.
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Affiliation(s)
- Po Ying Chia
- National Centre for Infectious Diseases, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore, Singapore
| | - Andrew Teo
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- Department of Medicine and Radiology and Doherty Institute, University of Melbourne, Victoria, VIC, Australia
| | - Tsin Wen Yeo
- National Centre for Infectious Diseases, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore, Singapore
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Wang D, Guo Y, Chai S, Shen K, Li Y, Zhao R. Expression of angiopoietin-like protein 2 in ovarian tissue of rat polycystic ovarian syndrome model and its correlation study. Reprod Biol Endocrinol 2020; 18:94. [PMID: 32988397 PMCID: PMC7520960 DOI: 10.1186/s12958-020-00651-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 09/17/2020] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND This study investigated the expression of angiopoietin-like protein 2 (ANGPTL2) in the tissues of rat models of polycystic ovary syndrome (PCOS) and its correlation with PCOS. METHODS Six-weeks-old female specific pathogen-free rats (n = 60) were divided into blank control, PCOS model, and metformin groups (n = 20/group). After 21 days of metformin intervention, the serum sex hormones, fasting blood glucose, fasting insulin, and insulin resistance (IR) of rats in each group were measured. The mRNA levels of ANGPTL2, Foxol, and Akt in the ovarian tissues were monitored by real-time fluorescence quantitative PCR. RESULTS Compared with the control group, the levels of serum sex hormones, fasting blood glucose, fasting insulin, and IR in the model group showed significant increases, and the levels of ANGPTL2, Foxol, and Akt in the ovarian tissue also showed significant increases. Compared with the PCOS group, the serum sex hormones, fasting blood glucose, fasting insulin, and IR of rats in the metformin group were significantly decreased, and the levels of ANGPTL2, Foxol, and Akt in ovarian tissues also showed significant decreases. CONCLUSIONS These findings suggest that ANGPTL2 might participate in the development of PCOS through the PI3K/Akt signaling pathway. Metformin improves IR by reducing the expression of ANGPTL2, thus improving the endocrine environment of PCOS and might change the disease outcome.
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Affiliation(s)
- Dandan Wang
- Reproduction Center, The Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Yihong Guo
- Reproductive and Genetic Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Shujuan Chai
- Reproduction Center, The Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Ke Shen
- Reproduction Center, The Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Yanchun Li
- Reproduction Center, The Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Ruiqin Zhao
- Reproduction Center, The Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
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Lu X. Structure and Function of Angiopoietin-like Protein 3 (ANGPTL3) in Atherosclerosis. Curr Med Chem 2020; 27:5159-5174. [PMID: 31223079 DOI: 10.2174/0929867326666190621120523] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 04/24/2019] [Accepted: 04/30/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Angiopoietin-Like Proteins (ANGPTLs) are structurally related to the angiopoietins. A total of eight ANGPTLs (from ANGPTL1 to ANGPTL8) have been identified so far. Most ANGPTLs possess multibiological functions on lipid metabolism, atherosclerosis, and cancer. Among them, ANGPTL3 has been shown to regulate the levels of Very Low-Density Lipoprotein (VLDL) made by the liver and play a crucial role in human lipoprotein metabolism. METHOD A systematic appraisal of ANGPTLs was conducted, focusing on the main features of ANGPTL3 that has a significant role in atherosclerosis. RESULTS Angiopoietins including ANGPTL3 are vascular growth factors that are highly specific for endothelial cells, perform a variety of other regulatory activities to influence inflammation, and have been shown to possess both pro-atherosclerotic and atheroprotective effects. CONCLUSION ANGPTL3 has been demonstrated as a promising target in the pharmacological management of atherosclerosis. However, many questions remain about its biological functions.
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Affiliation(s)
- Xinjie Lu
- The Mary and Garry Weston Molecular Immunology Laboratory, Thrombosis Research Institute, London SW3 6LR, England, United Kingdom
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20
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Keles A, Sonmez K, Erol YO, Ayyıldız SN, Ogus E. Vitreous levels of vascular endothelial growth factor, stromal cell-derived factor-1α, and angiopoietin-like protein 2 in patients with active proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2020; 259:53-60. [PMID: 32813109 DOI: 10.1007/s00417-020-04889-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/04/2020] [Accepted: 08/06/2020] [Indexed: 12/31/2022] Open
Abstract
PURPOSE To determine the vitreous levels of vascular endothelial growth factor (VEGF), stromal cell-derived factor-1α (SDF-1α) and angiopoietin-like protein 2 (ANGPTL2) in patients with active proliferative diabetic retinopathy (PDR), and to ascertain their contribution on different clinical presentation of active PDR. METHODS This case-control study included 31 eyes with active PDR and 10 eyes with idiopathic macular hole (MH) (control group). Eyes with active PDR were divided into three subgroups: vitreous hemorrhage (VH), tractional retinal detachment (TRD) caused by active fibrovascular membrane (FVM), and coexistence of VH and TRD with FVM. Vitreous samples obtained during vitrectomy were analyzed for concentrations of VEGF, SDF-1α, and ANGPTL2. RESULTS Vitreous level of VEGF (2021 (168-6550) pg/ml vs 110.1 (74.5-236) pg/ml), SDF-1α (517 (194-1044) pg/ml vs 388 (320-535) pg/ml), and ANGPTL2 (725 (131-1590) ng/ml vs 196 (75.9-437) ng/ml) were significantly higher in eyes with active PDR than in control group (p < 0.001, p = 0.002, and p < 0.001, respectively). The concentrations of these meaditors in each active PDR subgroups were also significantly higher than control group (p < 0.05). The vitreous level of ANGPTL2 was significantly higher in eyes with TRD caused by FVM (1033 ± 401 ng/ml) than in eyes with VH (561 ± 237 ng/ml; p = 0.008). CONCLUSION High levels of SDF-1α, ANGPTL2 and particularly VEGF seem to be associated with PDR. Since the vitreous levels of ANGPTL2 tend to be higher in eyes with active fibrovascular tractional detachment, vitreous levels of this chemokine seem to be affected by the clinical presentation of vascularly active PDR eyes.
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Affiliation(s)
- Ali Keles
- Department of Ophthalmology, Cizre State Hospital, Sırnak, Turkey
| | - Kenan Sonmez
- Ulucanlar Eye Training and Research Hospital, University of Health Sciences, Kale Mh. Ulucanlar Cd. No:59, 06250, Altındag, Ankara, Turkey.
| | - Yasemin Ozdamar Erol
- Ulucanlar Eye Training and Research Hospital, University of Health Sciences, Kale Mh. Ulucanlar Cd. No:59, 06250, Altındag, Ankara, Turkey
| | - Sema Nur Ayyıldız
- Department of Medical Biochemistry, Ankara Training and Research Hospital, Ankara, Turkey
| | - Elmas Ogus
- Department of Medical Biochemistry, Ankara Training and Research Hospital, Ankara, Turkey
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21
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Associations of cardiovascular biomarkers and plasma albumin with exceptional survival to the highest ages. Nat Commun 2020; 11:3820. [PMID: 32732919 PMCID: PMC7393489 DOI: 10.1038/s41467-020-17636-0] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Accepted: 07/07/2020] [Indexed: 12/22/2022] Open
Abstract
Supercentenarians (those aged ≥110 years) are approaching the current human longevity limit by preventing or surviving major illness. Identifying specific biomarkers conducive to exceptional survival might provide insights into counter-regulatory mechanisms against aging-related disease. Here, we report associations between cardiovascular disease-related biomarkers and survival to the highest ages using a unique dataset of 1,427 oldest individuals from three longitudinal cohort studies, including 36 supercentenarians, 572 semi-supercentenarians (105–109 years), 288 centenarians (100–104 years), and 531 very old people (85–99 years). During follow-up, 1,000 participants (70.1%) died. Overall, N-terminal pro-B-type natriuretic peptide (NT-proBNP), interleukin-6, cystatin C and cholinesterase are associated with all-cause mortality independent of traditional cardiovascular risk factors and plasma albumin. Of these, low NT-proBNP levels are statistically associated with a survival advantage to supercentenarian age. Only low albumin is associated with high mortality across age groups. These findings expand our knowledge on the biology of human longevity. Supercentenarians are approaching the current longevity limit by avoiding or surviving major illness, thus identifying biomarkers for exceptional survival might provide insights into the protection against disease of aging. Here, the authors show low NT-proBNP and high albumin in plasma are the biological correlates of survival to the highest ages.
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22
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Fan KC, Wu HT, Wei JN, Chuang LM, Hsu CY, Yen IW, Lin CH, Lin MS, Shih SR, Wang SH, Chang TJ, Li HY. Serum Angiopoietin-like Protein 6, Risk of Type 2 Diabetes, and Response to Hyperglycemia: A Prospective Cohort Study. J Clin Endocrinol Metab 2020; 105:5775438. [PMID: 32123920 DOI: 10.1210/clinem/dgaa103] [Citation(s) in RCA: 5] [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: 11/04/2019] [Accepted: 02/27/2020] [Indexed: 02/06/2023]
Abstract
CONTEXT Angiopoietin-like protein 6 (ANGPTL6) is a hepatokine that improves insulin sensitivity in animals. However, serum ANGPTL6 concentration was found to be higher in human participants with diabetes or metabolic syndrome in cross-sectional studies, implying that ANGPTL6 may be induced to counteract hyperglycemia. OBJECTIVE To investigate whether serum ANGPTL6 can predict incident diabetes and explore whether glucose or insulin can regulate ANGPTL6 expression and secretion. DESIGN This cohort study included adults without diabetes at baseline who were followed every 2 years for incident diabetes. Serum ANGPTL6 concentrations were measured at baseline and during oral glucose tolerance tests (OGTTs). A hepatic cell line, HepG2, and diet-induced obesity mouse model were used to evaluate the response of ANGPTL6 expression and secretion to hyperglycemia and the metabolic syndrome. RESULTS We recruited 1103 participants without diabetes at baseline. During the 4.22-year follow-up, 113 (10.2%) participants developed incident diabetes. Serum ANGPTL6 was negatively associated with the incidence of diabetes (adjusted hazard ratio, 0.77; P = 0.042). However, serum ANGPTL6 level was higher in participants with prediabetes (P = 0.018) and was elevated during OGTT. In HepG2 cells, treatment with glucose, but not insulin, induced ANGPTL6 expression. Hepatic ANGPTL6 expression and serum ANGPTL6 concentrations were significantly higher in mice fed with a high-fat diet than in those fed with a standard chow (both P < 0.05). CONCLUSION A high serum ANGPTL6 level is associated with a low incidence of diabetes in humans. ANGPTL6 is expressed and secreted in response to hyperglycemia to maintain glucose homeostasis.
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Affiliation(s)
- Kang-Chih Fan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hung-Tsung Wu
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan
| | - Jung-Nan Wei
- Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Lee-Ming Chuang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chih-Yao Hsu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - I-Weng Yen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - Chia-Hung Lin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - Mao-Shin Lin
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shyang-Rong Shih
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shu-Huei Wang
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tien-Jyun Chang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Yuan Li
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Hammad MM, Abu-Farha M, Al-Taiar A, Alam-Eldin N, Al-Sabah R, Shaban L, Al-Mulla F, Abubaker J, Rahman A. Correlation of circulating ANGPTL5 levels with obesity, high sensitivity C-reactive protein and oxidized low-density lipoprotein in adolescents. Sci Rep 2020; 10:6330. [PMID: 32286392 PMCID: PMC7156513 DOI: 10.1038/s41598-020-63076-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 03/24/2020] [Indexed: 12/12/2022] Open
Abstract
Angiopoietin-like proteins (ANGPTL) is a family of eight members known to play an important role in metabolic diseases. Of these, ANGPTL5 is suggested to regulate triglyceride metabolism and is increased in obesity and diabetes. However, its role in metabolic diseases in adolescents is not well-studied. In this study, we tested the hypothesis of a positive association between plasma ANGPTL5, and obesity, high sensitivity C-reactive protein (HsCRP) and oxidized low-density lipoprotein (Ox-LDL) in adolescents. Adolescents (N = 431; age 11–14 years) were randomly selected from middle schools in Kuwait. Obesity was classified by the BMI-for-age based on the WHO growth charts. Plasma ANGPTL5, HsCRP, and Ox-LDL were measured using ELISA. The prevalence of overweight and obesity was 20.65% and 33.18%, respectively. Mean (SD) plasma ANGPTL5 levels were significantly higher in obese, compared with overweight and normal-weight adolescents (23.05 (8.79) vs 18.39 (7.08) ng/mL, and 18.26 (6.95) ng/ml, respectively). ANGPTL5 was positively associated with both HsCRP (ρ=0.27, p < 0.001) and Ox-LDL (ρ = 0.24, p < 0.001). In Conclusion, ANGPTL5 levels are elevated in obese adolescents and are associated with cardiovascular disease risk factors, HsCRP and Ox-LDL. The use of ANGPTL5 as a powerful diagnostic and prognostic tool in obesity and metabolic diseases needs to be further evaluated.
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Affiliation(s)
- Maha M Hammad
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Mohamed Abu-Farha
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Abdullah Al-Taiar
- School of Community & Environmental Health, College of Health Sciences, Old Dominion University, Norfolk, VA, USA
| | - Nada Alam-Eldin
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Reem Al-Sabah
- Department of Community Medicine and Behavioural Sciences, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Lemia Shaban
- Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Kuwait City, Kuwait
| | - Fahd Al-Mulla
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Jehad Abubaker
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait.
| | - Abdur Rahman
- Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Kuwait City, Kuwait.
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Morelli MB, Chavez C, Santulli G. Angiopoietin-like proteins as therapeutic targets for cardiovascular disease: focus on lipid disorders. Expert Opin Ther Targets 2020; 24:79-88. [PMID: 31856617 DOI: 10.1080/14728222.2020.1707806] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Angiopoietin-like (ANGPTL) proteins belong to a family of eight secreted factors that are structurally related to proteins that modulate angiogenesi, commonly known as angiopoietins. Specifically, ANGPTL3, ANGPTL4, and ANGPTL8 (the 'ANGPT L3-4-8 triad'), have surfaced as principal regulators of plasma lipid metabolism by functioning as potent inhibitors of lipoprotein lipase. The targeting of these proteins may open up future therapeutic avenues for metabolic and cardiovascular disease.Areas covered: This article systematically summarizes the compelling literature describing the mechanistic roles of ANGPTL3, 4, and 8 in lipid metabolism, emphasizing their importance in determining the risk of cardiovascular disease. We shed light on population-based studies linking loss-of-function variations in ANGPTL3, 4, and 8 with decreased risk of metabolic conditions and cardiovascular disorders. We also discuss how the strategies aiming at targeting the ANGPT L3-4-8 triad could offer therapeutic benefit in the clinical scenario.Expert opinion: Monoclonal antibodies and antisense oligonucleotides that target ANGPTL3, 4, and 8 are potentially an efficient therapeutic strategy for hypertriglyceridemia and cardiovascular risk reduction, especially in patients with limited treatment options. These innovative therapeutical approaches are at an embryonic stage in development and hence further investigations are necessary for eventual use in humans.
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Affiliation(s)
- Marco Bruno Morelli
- Department of Medicine; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY, USA.,Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), The "Norman Fleischer" Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, NY, New York, USA
| | - Christopher Chavez
- Department of Medicine; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY, USA
| | - Gaetano Santulli
- Department of Medicine; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY, USA.,Department of Molecular Pharmacology, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), The "Norman Fleischer" Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, NY, New York, USA.,Department of Advanced Biomedical Sciences and International Translational Research and Medical Education Consortium (ITME), "Federico II" University, Naples, Italy
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25
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El-Lebedy D. Association of serum angiopoietin-like protein 2 with elevated risk of cardiovascular diseases in subjects with type 2 diabetes. J Diabetes Complications 2019; 33:107421. [PMID: 31484627 DOI: 10.1016/j.jdiacomp.2019.107421] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 08/17/2019] [Indexed: 12/12/2022]
Abstract
AIMS Although previous data have suggested ANGPTL2 and ANGPTL8 (betatrophin) to be related to atherosclerosis in humans, little is known whether this applies in patients with type 2 diabetes (T2D). In this work, we investigate association of serum ANGPTL2 and betatrophin with the risk of cardiovascular diseases (CVD) in T2D patients. METHODS We measured serum levels of ANGPTL2 and betatrophin in 150 T2D patients with and without CVD and in 100 control subjects. RESULTS Serum ANGPTL2 was significantly higher in T2D patients than in controls (p < 0.0001), and in T2D + CVD patients than T2D only patients (p = 0.0002). Serum betatrophin was lower in T2D patients than in controls but with no statistical significance (p = 0.07). Elevated serum ANGPTL2 associated with 2.83-fold increased risk of T2D and with 1.18-fold elevated risk of CVD among T2D patients with positive correlations with markers of hyperglycemia, insulin resistance and atherogenic lipid profile. ROC curve indicated ANGPTL2 as risk biomarker for T2D and CVD with sensitivity of 92.2% and 86%; and specificity of 86.7% and 58%; respectively. CONCLUSION We indicate for the first time serum ANGPTL2 as an independent risk biomarker for CVD in T2D patients. Future studies are needed to reveal its role in disease pathogenesis.
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Affiliation(s)
- Dalia El-Lebedy
- Department of Clinical and Chemical Pathology, Medical Research Division, National Research Center, Cairo, Egypt.
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26
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Pinzone MR, Ceccarelli M, Venanzi Rullo E, Maresca M, Bruno R, Condorelli F, Di Rosa M, Madeddu G, Focà E, Calcagno A, Celesia BM, Cacopardo B, Nunnari G, Pellicanò GF. Circulating angiopoietin-like protein 2 levels are associated with decreased renal function in HIV + subjects on cART: A potential marker of kidney disease. Biomed Rep 2019; 10:140-144. [PMID: 30675354 PMCID: PMC6341407 DOI: 10.3892/br.2019.1183] [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: 11/27/2018] [Accepted: 01/07/2019] [Indexed: 12/17/2022] Open
Abstract
Chronic kidney disease (CKD) is an important cause of morbidity and mortality in HIV-infected individuals, even in the antiretroviral therapy (ART) era. Inflammatory cytokines and adipokines have been suggested to play a role in the development of CKD. The aim of the present study was to examine the circulating levels of a novel proinflammatory cytokine, angiopoietin-like protein 2 (ANGPTL2), in a cohort of 72 HIV-positive subjects on ART. HIV-positive patients were on cART for at least one year. Urine and blood samples were collected. Various factors were analyzed including body mass index (BMI), smoking, and presence/treatment for comorbidities such as diabetes. The estimated glomerular filtration rate was calculated by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Plasma samples obtained were stored and used to measure sCD14 and ANGPTL2 levels. Data were presented as mean (± standard deviation) or median (interquartile range) for continuous variables. Categorical variables were expressed as number (%). Variables were compared using Student's t-test, Mann-Whitney test, or χ2 test. The results showed an independent negative association between plasma ANGPTL2 and CKD-EPI values. Further prospective studies on larger cohorts are needed to evaluate the pathogenetic role of ANGPTL2 as well as its use as a diagnostic marker of renal dysfunction.
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Affiliation(s)
- Marilia Rita Pinzone
- Department of Clinical and Experimental Medicine, Division of Infectious Diseases, University of Catania, I-95123 Catania, Italy
- Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Manuela Ceccarelli
- Department of Clinical and Experimental Medicine, Unit of Infectious Diseases, University of Messina, I-98124 Messina, Italy
| | - Emmanuele Venanzi Rullo
- Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Clinical and Experimental Medicine, Unit of Infectious Diseases, University of Messina, I-98124 Messina, Italy
| | - Mauro Maresca
- Department of Clinical and Experimental Medicine, Division of Infectious Diseases, University of Catania, I-95123 Catania, Italy
| | - Roberto Bruno
- Department of Clinical and Experimental Medicine, Division of Infectious Diseases, University of Catania, I-95123 Catania, Italy
| | - Fabrizio Condorelli
- Department of Pharmacological Sciences, University of Eastern Piedmont ‘A. Avogadro’, I-13100 Novara, Italy
| | - Michele Di Rosa
- Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, University of Catania, I-95123 Catania, Italy
| | - Giordano Madeddu
- Department of Medical, Surgical and Experimental Sciences, Division of Infectious Diseases, University of Sassari, I-07100 Sassari, Italy
| | - Emanuele Focà
- Department of Clinical and Experimental Sciences, Division of Infectious Diseases, University of Brescia, I-25121 Brescia, Italy
| | - Andrea Calcagno
- Department of Medical Sciences, Unit of Infectious Diseases, University of Torino, I-10124 Torino, Italy
| | - Benedetto Maurizio Celesia
- Department of Clinical and Experimental Medicine, Division of Infectious Diseases, University of Catania, I-95123 Catania, Italy
| | - Bruno Cacopardo
- Department of Clinical and Experimental Medicine, Division of Infectious Diseases, University of Catania, I-95123 Catania, Italy
| | - Giuseppe Nunnari
- Department of Clinical and Experimental Medicine, Unit of Infectious Diseases, University of Messina, I-98124 Messina, Italy
| | - Giovanni F. Pellicanò
- Department of Human Pathology in Adult and Developmental Age ‘G. Barresi’, University of Messina, I-98124 Messina, Italy
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Noly PE, Labbé P, Thorin-Trescases N, Fortier A, Nguyen A, Thorin E, Carrier M. Reduction of plasma angiopoietin-like 2 after cardiac surgery is related to tissue inflammation and senescence status of patients. J Thorac Cardiovasc Surg 2019; 158:792-802.e5. [PMID: 30745045 DOI: 10.1016/j.jtcvs.2018.12.047] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 12/04/2018] [Accepted: 12/15/2018] [Indexed: 12/17/2022]
Abstract
OBJECTIVES A strong relationship between high circulating angiopoietin-like 2 (ANGPTL2) levels, a proinflammatory adipokine, and cardiovascular diseases has been reported. Our objective was to determine whether plasma ANGPTL2 and high-sensitivity C-reactive protein (hs-CRP) levels change postoperatively in patients who underwent heart valve surgery and/or coronary artery bypass grafting. We hypothesized that a corrective cardiac surgery would decrease ANGPTL2 levels. METHODS In 47 prospectively recruited patients who underwent coronary artery bypass grafting (n = 16), valve replacement (n = 16), or both (n = 15), we measured plasma ANGPTL2 and hs-CRP levels preoperatively, at 24 hours, at 3 to 5 days (hospital discharge), and at 30 to 90 days (follow-up) after surgery. Mediastinal adipose tissue and distal fragments of the left internal mammary artery (IMA) were harvested during surgery and mRNA expression of inflammatory and senescence markers was assessed using real-time quantitative polymerase chain reaction. RESULTS ANGPTL2 and hs-CRP levels were elevated 24 hours after surgery and then returned to baseline levels. We noted, however, a dichotomy among patients: compared with baseline, plasma ANGPTL2 levels either significantly decreased (n = 21/47) or increased (n = 26/47) after surgery. In contrast, hs-CRP levels were identical between groups (P = .997). Patients in the increased group were older (P = .002) with a higher systolic blood pressure (P = .038) at baseline. Moreover, changes in ANGPTL2 levels (ΔANGPTL2 = final minus initial levels) positively correlated with mRNA expression of tumor necrosis factor α and interleukin 8 in mediastinal adipose tissue and IMA (P < .05) and with the senescence-associated marker cyclin-dependent kinase inhibitor 1 in IMA (P = .009). CONCLUSIONS In younger patients with lower levels of tissue inflammation and arterial senescence load, ANGPTL2, but not hs-CRP levels decreased after cardiac surgery, suggesting that circulating ANGPTL2 reflects tissue inflammation and senescence.
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Affiliation(s)
- Pierre-Emmanuel Noly
- Faculty of Medicine, Department of Surgery, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Pauline Labbé
- Montreal Heart Institute Research Center, Université de Montréal, Montreal, Quebec, Canada; Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada
| | | | - Annik Fortier
- Montreal Health Innovations Coordinating Center, Montreal, Quebec, Canada
| | - Albert Nguyen
- Montreal Heart Institute Research Center, Université de Montréal, Montreal, Quebec, Canada
| | - Eric Thorin
- Faculty of Medicine, Department of Surgery, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada.
| | - Michel Carrier
- Faculty of Medicine, Department of Surgery, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
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Yoshinaga T, Niou T, Niihara T, Kajiya Y, Hori E, Tomiyoshi A, Tokudome E, Nishimata H, Takei T, Yoshida M. Angiopoietin-like Protein 2 is a Useful Biomarker for Pancreatic Cancer that is Associated with Type 2 Diabetes Mellitus and Inflammation. J Cancer 2018; 9:4736-4741. [PMID: 30588259 PMCID: PMC6299393 DOI: 10.7150/jca.25404] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer is one of the tumors with the worst prognosis, with the 5-year survival rate reported to be 6%. The number of patients suffering from pancreatic cancer in recent years has continued to increase dramatically. Carbohydrate antigen 19-9 is an established biomarker of pancreatic cancer, but it does not have sufficient ability to detect pancreatic cancer at an early stage. We focused on angiopoietin-like protein 2 (ANGPTL2), which has been reported to be related to chronic inflammation and Type 2 diabetes mellitus. In this study, whether ANGPTL2 can detect early pancreatic cancer was evaluated. It was found that the concentration of serum ANGPTL2 was significantly higher in pancreatic cancer patients and tumor stage 0-I patients than in healthy individuals (5.84 ± 1.82 ng/mL vs 3.61 ± 0.64 ng/mL; P < 0.001) (5.68 ± 0.79 ng/mL vs 3.61 ± 0.64 ng/mL; P = 0.010). In addition, the diagnostic capability of serum ANGPTL2 levels for pancreatic cancer was evaluated using receiver operating characteristic (ROC) curve analysis. The area under the ROC curve (AUC) for ANGPTL2 was 0.906 (95% confidence interval (CI): 0.815-0.997; P < 0.001). To identify the risk factors for pancreatic cancer, multivariate regression models were used. Ten factors were included, and increasing age (odds ratio (OR), 1.318, 95% CI, 1.058-1.642; P = 0.014) and high ANGPTL2 levels (OR, 22.219, 95% CI, 1.962-251.659, P = 0.012) were found to be independent risk factors for pancreatic cancer, with ANGPTL2 having the strongest relationship. In addition, serum ANGPTL2 levels were strongly correlated with inflammatory markers, with blood sugar levels showing the strongest correlation with serum ANGPTL2 levels. In conclusion, this study suggested that an elevated serum ANGPTL2 level has the potential to be a biomarker capable of early detection of pancreatic cancer, and it was correlated with inflammation of the pancreas and the risk of developing diabetes mellitus.
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Affiliation(s)
- Takuma Yoshinaga
- Division of Clinical Application, Nanpuh Hospital, Kagoshima, Japan
| | | | - Toru Niihara
- Gastroenterology, Nanpuh Hospital, Kagoshima, Japan
| | - Yoriko Kajiya
- Department of Radiology, Nanpuh Hospital, Kagoshima, Japan
| | - Emiko Hori
- Division of Clinical Application, Nanpuh Hospital, Kagoshima, Japan
| | - Ayako Tomiyoshi
- Division of Clinical Application, Nanpuh Hospital, Kagoshima, Japan
| | - Erena Tokudome
- Division of Clinical Application, Nanpuh Hospital, Kagoshima, Japan
| | | | - Takayuki Takei
- Department of Chemical Engineering, Graduate School of Science and Engineering, Kagoshima, Japan
| | - Masahiro Yoshida
- Department of Chemical Engineering, Graduate School of Science and Engineering, Kagoshima, Japan
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Suzuki T, Takebayashi K, Hara K, Tsuchiya T, Inukai T. Association between angiopoietin-like protein 2 and lectin-like oxidized low-density lipoprotein receptor 1 ligand containing apolipoprotein B in patients with type 2 diabetes. J Int Med Res 2018; 46:4167-4180. [PMID: 30157689 PMCID: PMC6166345 DOI: 10.1177/0300060518791067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Objective This study was performed to evaluate the association of the serum level of
angiopoietin-like protein 2 (ANGPTL2) with circulating inflammatory markers
and oxidized and modified low-density lipoprotein (LDL) cholesterol as
evaluated by lectin-like oxidized LDL receptor 1 ligand containing
apolipoprotein B (LAB) in patients with type 2 diabetes. Methods The study included 70 patients with type 2 diabetes hospitalized for glycemic
control and 9 control subjects. Results The serum level of ANGPTL2 was significantly higher in the patients with type
2 diabetes than in the healthy controls. There was a significant positive
correlation between ANGPTL2 and the high-sensitivity C-reactive protein,
fibrinogen, and LAB levels and a significant negative correlation between
ANGPTL2 and the estimated glomerular filtration rate (eGFR). Conclusions These results suggest that the serum ANGPTL2 level has a close positive
association with inflammatory markers, especially fibrinogen and oxidized
and modified LDL as evaluated by LAB. The data also suggest that the serum
ANGPTL2 level is influenced by renal function as reflected by the eGFR.
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Affiliation(s)
- Tatsuhiko Suzuki
- Department of Internal Medicine, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, Japan
| | - Kohzo Takebayashi
- Department of Internal Medicine, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, Japan
| | - Kenji Hara
- Department of Internal Medicine, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, Japan
| | - Takafumi Tsuchiya
- Department of Internal Medicine, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, Japan
| | - Toshihiko Inukai
- Department of Internal Medicine, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, Japan
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Enhanced ANGPTL2 expression in adipose tissues and its association with insulin resistance in obese women. Sci Rep 2018; 8:13976. [PMID: 30228336 PMCID: PMC6143523 DOI: 10.1038/s41598-018-32419-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 09/07/2018] [Indexed: 12/27/2022] Open
Abstract
Angiopoietin-like protein 2 has been proposed to be a key mediator linking obesity and insulin resistance. However, no detailed study of ANGPTL2 expression in human adipose tissues has yet been reported. To investigate the pattern and regulation of ANGPTL2 expression in human adipose tissues in obesity and its related diseases, we recruited 32 non-diabetic and 13 type 2 diabetic obese women and 32 normal-weight women. ANGPTL2 mRNA was expressed at a similar level in visceral and subcutaneous adipose tissues. Adipose tissue ANGPTL2 mRNA was much higher in obese patients. Adipose tissue ANGPTL2 mRNA and serum ANGPTL2 levels showed strong associations with metabolic parameters associated with insulin resistance. In adipose tissue, ANGPTL2 mRNA was closely correlated with the expression of genes involved in inflammation and ER stress. ANGPTL2 mRNA was principally expressed in adipocytes, and its expression was markedly higher in the adipocyte but non-adipocyte fraction of obese adipose tissues. Culture of human adipocytes under conditions mimicking the microenvironment of obese adipose tissue (especially, increased ER stress) stimulated ANGPTL2 gene expression and secretion. In addition, co-culture of adipocytes and macrophages suggested that ANGPTL2 excessively produced by adipocytes, may contribute inflammation and remodeling in obese adipose tissues, thereby promoting insulin resistance.
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Gonzalez LL, Garrie K, Turner MD. Type 2 diabetes - An autoinflammatory disease driven by metabolic stress. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3805-3823. [PMID: 30251697 DOI: 10.1016/j.bbadis.2018.08.034] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 08/27/2018] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes has traditionally been viewed as a metabolic disorder characterised by chronic high glucose levels, insulin resistance, and declining insulin secretion from the pancreas. Modern lifestyle, with abundant nutrient supply and reduced physical activity, has resulted in dramatic increases in the rates of obesity-associated disease conditions, including diabetes. The associated excess of nutrients induces a state of systemic low-grade chronic inflammation that results from production and secretion of inflammatory mediators from the expanded pool of activated adipocytes. Here, we review the mechanisms by which obesity induces adipose tissue dysregulation, detailing the roles of adipose tissue secreted factors and their action upon other cells and tissues central to glucose homeostasis and type 2 diabetes. Furthermore, given the emerging importance of adipokines, cytokines and chemokines in disease progression, we suggest that type 2 diabetes should now be viewed as an autoinflammatory disease, albeit one that is driven by metabolic dysregulation.
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Affiliation(s)
- Laura L Gonzalez
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom
| | - Karin Garrie
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom
| | - Mark D Turner
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom.
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Impact of serum cholesterol esterification rates on the development of diabetes mellitus in a general population. Lipids Health Dis 2018; 17:180. [PMID: 30055622 PMCID: PMC6064622 DOI: 10.1186/s12944-018-0822-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 07/10/2018] [Indexed: 11/12/2022] Open
Abstract
Background Lecithin:cholesterol acyltransferase (LCAT) plays an important role in cholesterol esterification in serum. Serum LCAT activity is elevated in patients with serum high triglyceride and low high-density lipoprotein-cholesterol (HDL-C) concentrations, both of which are related to metabolic syndrome and subsequent diabetes mellitus, referred to as lipotoxicity. We hypothesized that increased serum LCAT activity could predict future risk of diabetes mellitus in a general Japanese population. Methods We prospectively studied 1496 individuals aged 20–86 years without histories of diabetes mellitus at baseline. Serum lipid concentrations, glucose parameters, and LCAT activity measured as the serum cholesterol esterification rate, were evaluated. Results During 11 years of follow-up, 46 newly diagnosed patients with diabetes mellitus were reported. After adjustment for plasma glycosylated hemoglobin A1c (HbA1c) levels, the relative risks (RRs) for the development of diabetes mellitus were 5.45 [95% confidence interval (95% CI) 2.37–12.55; P < 0.001] for body-mass index, 0.22 (95% CI, 0.09–0.53; P = 0.001) for HDL-C, 4.81 (95% CI, 1.96–11.77; P = 0.001) for triglyceride, and 4.64 (95% CI, 1.89–11.41; P = 0.001) for LCAT activity. After adjustment for HbA1c, total cholesterol, triglyceride, HDL-C, phospholipid, and free fatty acid levels, the RR of LCAT activity for future risk of diabetes mellitus remained significant (RR, 4.93; 95% CI,1.32–18.41; P = 0.018). In this analysis, we found a significant association between LCAT activity and risk of diabetes mellitus in men but not in women. Conclusion Increased serum cholesterol esterification rate is a potent predictor for future diabetes mellitus.
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ANGPTL2 deletion inhibits osteoclast generation by modulating NF-κB/MAPKs/Cyclin pathways. Biochem Biophys Res Commun 2018; 503:1471-1477. [PMID: 30031603 DOI: 10.1016/j.bbrc.2018.07.065] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 07/12/2018] [Indexed: 02/05/2023]
Abstract
Osteoclasts are multinucleated cells essential for bone-resorption. Successful repair of bone defciencies still remains a great challenge worldwide. The signaling factor angiopoietin-like protein 2 (ANGPTL2), one of eight ANGPTL proteins, functions in maintenance of tissue homeostasis partly through regulating inflammation. In the study, ANGPTL2 expression was promoted during osteoclast development and that suppressing ANGPTL2 alleviated osteoclast production regulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). The results suggested that ANGPTL2 knockdown inhibited M-CSF-caused proliferation of osteoclast precursor cells. Further, ANGPTL2 silence reduced nuclear factor of activated T cell c 1 (NFATC1) and NFATC4 expressions in M-CSF-treated cells, along with decreased Runx2, OPN and Colla1. Moreover, silencing ANGPTL2 down-regulated M-CSF-promoted expressions of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and chemoattractant protein-1 (CCL-2). Consistently, ANGPTL2 knockdown reduced M-CSF-enhanced activation of IKKα, IκBα and nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) (p38 MAPK, ERK1/2 MAPK and JNK MAPK). Additionally, knockdown of ANGPTL2 inhibited the induction of Cyclin D1, Cyclin D2 and Cyclin E1 due to M-CSF exposure. In vivo, we confirmed that ANGPTL2 knockout (KO) mice were protected against osteoporosis induced by ovariectomy (OVX), as proved by the improved bone loss and bone mineral density (BMD). Decreased expression of NFATCs was also observed in OVX-induced mice in the absence of ANGPTL2. Elevated release of pro-inflammatory cytokines was abrogated by ANGPTL2 knockout in femoral heads of mice with OVX operation, accompanied with a significant reduction of phosphorylated NF-κB and MAPKs signaling pathways. And down-regulated expression of Cyclin D1, Cyclin D2 and Cyclin E1 was observed in OVX-operated mice with ANGPTL2 knockout. Therefore, our study indicated that ANGPTL2 played an essential role in osteoclast generation through regulating the proliferation and inflammation of osteoclast lineage cells, providing new insights into the therapeutic strategy to alleviate bone loss.
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Rahmani E, Akbarzadeh S, Broomand A, Torabi F, Motamed N, Zohrabi M. Serum Levels of Angiopoietin-Like Protein 2 and Obestatin in Iranian Women with Polycystic Ovary Syndrome and Normal Body Mass Index. J Clin Med 2018; 7:jcm7070159. [PMID: 29932432 PMCID: PMC6069096 DOI: 10.3390/jcm7070159] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/16/2018] [Accepted: 06/17/2018] [Indexed: 11/16/2022] Open
Abstract
Background: Polycystic ovary syndrome (PCOS) is a common endocrine disease in women of reproduction age and a major cause of anovulatory infertility. Insulin resistance plays an important role in the development and durability of this disorder. ANGPTL2 is known as an inflammatory mediator derived from adipose tissue that links obesity to systemic insulin resistance, and obestatin has been identified as a hormone associated with insulin resistance that suppresses food reabsorption, inhibits gastric emptying and decreases weight gain. The aim of this study was to evaluate serum levels of ANGPTL2 and obestatin in PCOS women with normal body mass index (BMI). Methods: In this case-control study, 26 PCOS women based on the Rotterdam 2003 diagnostic criteria as the case group and 26 women with normal menstrual cycles as the control group were enrolled. Serum levels of ANGPTL2, obestatin, insulin and other hormone factors related with PCOS were measured by ELISA method and biochemical parameters were measured by an autoanalyzer. Data were analyzed by independent samples-T test, Chi Square, Correlation and a single sample Kolmogrov–Smirnov test using SPSS software, version 16. Results: There were no significant variations in the amount of ANGPTL2, obestatin, cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein, cholesterol, creatinine and dehydroepiandrosterone-sulfate between the two groups. There were significant increases in serum levels of fasting blood sugar (p = 0.01), insulin (p = 0.04), homeostasis model assessments of insulin resistance (p = 0.04), testosterone (p = 0.02), luteinizing hormone (p = 0.004), luteinizing hormone/follicle stimulating hormone (p = 0.006) and prolactin (p = 0.04) in case group compared to the control group. A significant positive correlation was observed between ANGPTL2 and insulin (p = 0.02), HOMA-IR (p = 0.01) and, on the other hand, a significant negative correlation was observed between obestatin and insulin (p = 0.01), HOMA-IR (p = 0.008) in PCOS group. Conclusions: In this study, no significant variations were observed in serum levels of ANGPTL2 and obestatin in PCOS women with normal BMI.
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Affiliation(s)
- Elham Rahmani
- Department of Obstetrics and Gynecology, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr 7518759577, Iran.
| | - Samad Akbarzadeh
- Department of Biochemistry, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr 7518759577, Iran.
| | - Ainaz Broomand
- Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr 7518759577, Iran.
| | - Fatemeh Torabi
- Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr 7518759577, Iran.
| | - Niloofar Motamed
- Department of Community Medicine, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr 7518759577, Iran.
| | - Marzieh Zohrabi
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514947932, Iran.
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Yang W, Liu W, Yu W, Fei D, Meng X, Yang S, Meng S, Zhao M. Angptl2 deficiency attenuates paraquat (PQ)-induced lung injury in mice by altering inflammation, oxidative stress and fibrosis through NF-κB pathway. Biochem Biophys Res Commun 2018; 503:94-101. [PMID: 29852175 DOI: 10.1016/j.bbrc.2018.05.186] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 05/28/2018] [Indexed: 12/13/2022]
Abstract
Paraquat (PQ) is one of the most extensively used herbicides, possessing high toxicity for humans and animals. The lung is the main target organ by the poisoning of PQ resulting in acute lung injury. Nonetheless, molecular mechanisms underlying PQ-induced lung injury remain unclear. Here, we ask if angiopoietin-like protein 2 (Angptl2), a pro-inflammatory protein, contributes to inflammation that accelerates acute lung injury. The results indicated that abundant Angptl2 expression was observed in lung tissues of PQ-treated mice. Histological analysis revealed that PQ-induced histological changes were alleviated by Angptl2 knockout (Angptl2-/-). Angptl2-/- in PQ-treated mice attenuated acute lung injury progression by reducing the number of total cells, total leukocytes, neutrophils and macrophages in bronchoalveolar lavage fluid (BALF) and reducing inflammatory response through the inactivation of nuclear factor kappa B (NF-κB) pathway. Angptl2-/- reduced oxidative stress in PQ-treated mice, as evidenced by the enhanced superoxide dismutase (SOD) activity and reduced malondialdehyde (MDA) levels in serum or lung tissue samples, which was accompanied with increased expressions of nuclear respiratory factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1). PQ-induced fibrosis was also improved in Angptl2-/- mice by decreasing pulmonary transforming growth factor (TGF)-β1 expressions. In vitro, we found that Angptl2 knockdown-suppressed inflammation, oxidative stress and fibrosis was restored by increasing NF-κB activation in PQ-incubated A549 cells; however, the results above were significantly reversed by inactivating NF-κB using its inhibitor, Bay 11-7085 or LY2409881. Therefore, Angptl2 could provide therapeutic effects on PQ-induced acute lung injury through inhibiting inflammation, oxidative stress and fibrosis by regulating NF-κB pathway.
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Affiliation(s)
- Wei Yang
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, YouZheng Street, Nangang District, Harbin, 150001, China
| | - Wen Liu
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, YouZheng Street, Nangang District, Harbin, 150001, China; Department of General Surgery, Xinxiang Medical University, No. 601, New Yan Road, Xinxiang 453000, China
| | - Wei Yu
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, YouZheng Street, Nangang District, Harbin, 150001, China
| | - Dongsheng Fei
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, YouZheng Street, Nangang District, Harbin, 150001, China
| | - Xianglin Meng
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, YouZheng Street, Nangang District, Harbin, 150001, China
| | - Songlin Yang
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, YouZheng Street, Nangang District, Harbin, 150001, China
| | - Shishuai Meng
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, YouZheng Street, Nangang District, Harbin, 150001, China
| | - Mingyan Zhao
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, No. 23, YouZheng Street, Nangang District, Harbin, 150001, China.
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Martel C, Pinçon A, Bélanger AM, Luo X, Gillis MA, de Montgolfier O, Thorin-Trescases N, Thorin É. Knockdown of angiopoietin-like 2 mimics the benefits of intermittent fasting on insulin responsiveness and weight loss. Exp Biol Med (Maywood) 2017; 243:45-49. [PMID: 29192516 DOI: 10.1177/1535370217745505] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Angiopoietin-like 2 (ANGPTL2) is an inflammatory adipokine linking obesity to insulin resistance. Intermittent fasting, on the other hand, is a lifestyle intervention able to prevent obesity and diabetes but difficult to implement and maintain. Our objectives were to characterize a link between ANGPTL2 and intermittent fasting and to investigate whether the knockdown of ANGPTL2 reproduces the benefits of intermittent fasting on weight gain and insulin responsiveness in knockdown and wild-type littermates mice. Intermittent fasting, access to food ad libitum once every other day, was initiated at the age of three months and maintained for four months. Intermittent fasting decreased by 63% (p < 0.05) gene expression of angptl2 in adipose tissue of wild-type mice. As expected, intermittent fasting improved insulin sensitivity (p < 0.05) and limited weight gain (p < 0.05) in wild-type mice. Knockdown mice fed ad libitum, however, were comparable to wild-type mice following the intermittent fasting regimen: insulin sensitivity and weight gain were identical, while intermittent fasting had no additional impact on these parameters in knockdown mice. Energy intake was similar between both wild-type fed intermittent fasting and ANGPTL2 knockdown mice fed ad libitum, suggesting that intermittent fasting and knockdown of ANGPTL2 equally lower feeding efficiency. These results suggest that the reduction of ANGPTL2 could be a useful and promising strategy to prevent obesity and insulin resistance, although further investigation of the mechanisms linking ANGPTL2 and intermittent fasting is warranted. Impact statement Intermittent fasting is an efficient diet pattern to prevent weight gain and improve insulin sensitivity. It is, however, a difficult regimen to follow and compliance is expected to be very low. In this work, we demonstrate that knockdown of ANGPTL2 in mice fed ad libitum mimics the beneficial effects of intermittent fasting on weight gain and insulin sensitivity in wild-type mice. ANGPTL2 is a cytokine positively associated with fat mass in humans, which inactivation in mice improves resistance to a high-fat metabolic challenge. This study provides a novel pathway by which IF acts to limit obesity despite equivalent energy intake. The development of a pharmacological ANGPTL2 antagonist could provide an efficient tool to reduce the burden of obesity.
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Affiliation(s)
- Cécile Martel
- 1 Montreal Heart Institute, Research Center, 12368 University of Montreal , Montreal, QC H1T 1C8, Canada
| | - Anthony Pinçon
- 1 Montreal Heart Institute, Research Center, 12368 University of Montreal , Montreal, QC H1T 1C8, Canada
| | - Alexandre Maxime Bélanger
- 1 Montreal Heart Institute, Research Center, 12368 University of Montreal , Montreal, QC H1T 1C8, Canada
| | - Xiaoyan Luo
- 1 Montreal Heart Institute, Research Center, 12368 University of Montreal , Montreal, QC H1T 1C8, Canada
| | - Marc-Antoine Gillis
- 1 Montreal Heart Institute, Research Center, 12368 University of Montreal , Montreal, QC H1T 1C8, Canada
| | - Olivia de Montgolfier
- 2 Departments of Surgery and Pharmacology, Faculty of Medicine, 12368 University of Montreal , Montréal H3T 1J4, QC, Canada
| | - Nathalie Thorin-Trescases
- 1 Montreal Heart Institute, Research Center, 12368 University of Montreal , Montreal, QC H1T 1C8, Canada
| | - Éric Thorin
- 1 Montreal Heart Institute, Research Center, 12368 University of Montreal , Montreal, QC H1T 1C8, Canada.,2 Departments of Surgery and Pharmacology, Faculty of Medicine, 12368 University of Montreal , Montréal H3T 1J4, QC, Canada
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Oike Y, Tian Z, Miyata K, Morinaga J, Endo M, Kadomatsu T. ANGPTL2 - A New Causal Player in Accelerating Heart Disease Development in the Aging. Circ J 2017; 81:1379-1385. [PMID: 28867689 DOI: 10.1253/circj.cj-17-0854] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In parallel with the increase in the number of elderly people worldwide, the number of patients with heart disease is also rapidly increasing. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are strongly associated with adverse health outcomes that decrease productivity in later years. Recently, ANGPTL2, a secreted glycoprotein and member of the angiopoietin-like protein family, has received attention as a causal player in the development of CVD and HF. Prolonged ANGPTL2 autocrine/paracrine signaling in vascular tissue leads to chronic inflammation and pathologic tissue remodeling, accelerating CVD development. Excess ANGPTL2 autocrine/paracrine signaling induced in the pathologically stressed heart accelerates cardiac dysfunction by decreasing myocardial energy metabolism. Conversely, ANGPTL2 inactivation in vascular tissue and the heart delays development or progression of CVD and HF, respectively. Moreover, there is increased evidence for an association between elevated circulating ANGPTL2 levels and CVD and HF. Interestingly, ANGPTL2 expression is also associated with cellular senescence, which may promote premature aging and development of aging-associated diseases, including CVD and HF. Overall, ANGPTL2 autocrine/paracrine signaling is a new factor in accelerating heart disease development in the aging. Here, we focus on current topics relevant to ANGPTL2 function in heart disease.
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Affiliation(s)
- Yuichi Oike
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University
| | - Zhe Tian
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University
| | - Keishi Miyata
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University
| | - Jun Morinaga
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University
| | - Motoyoshi Endo
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University
| | - Tsuyoshi Kadomatsu
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University
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High Circulating Levels of ANGPTL2: Beyond a Clinical Marker of Systemic Inflammation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:1096385. [PMID: 29138671 PMCID: PMC5613648 DOI: 10.1155/2017/1096385] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 07/25/2017] [Accepted: 08/02/2017] [Indexed: 12/18/2022]
Abstract
Angiopoietin-like 2 (ANGPTL2) is a proinflammatory protein belonging to the angiopoietin-like family. ANGPTL2 is secreted and detected in the systemic circulation. Different observational clinical studies reported that circulating levels of ANGPTL2 increase significantly in various chronic inflammatory diseases and showed associations between ANGPTL2 levels and diagnosis and/or prognosis of cardiovascular diseases, diabetes, chronic kidney disease, and various types of cancers. However, these studies did not address the following questions: (a) what are the sources of circulating ANGPTL2? (b) How and by which mechanisms an increase in circulating ANGPTL2 contributes to the pathogenesis of chronic inflammatory diseases? (c) Does an increase in circulating levels of ANGPTL2 measured in a well-defined chronic medical condition originate from a specific cell type? Mechanistic hypotheses have been proposed based on studies performed in mice and cultured cells, and proinflammatory, prooxidative, proangiogenic, proliferative, and antiapoptotic properties of ANGPTL2 have been reported. The aim of this review is to propose answers concerning the potential sources of circulating ANGPTL2 and its common pathological properties associated with various chronic inflammatory diseases and death in humans. We believe that high circulating ANGPTL2 levels are more than an inflammatory marker and may reflect the senescent cellular load of an individual.
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Piché ME, Thorin-Trescases N, Auclair A, Marceau S, Martin J, Fortier A, Thorin E, Poirier P. Bariatric Surgery-Induced Lower Angiopoietin-Like 2 Protein Is Associated With Improved Cardiometabolic Profile. Can J Cardiol 2017; 33:1044-1051. [PMID: 28754390 DOI: 10.1016/j.cjca.2017.05.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Revised: 05/26/2017] [Accepted: 05/08/2017] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Plasma angiopoietin-like 2 (Angptl2), a proinflammatory protein, has been associated with obesity and diabetes. Whether weight loss induced by bariatric surgery and associated improvement of the cardiometabolic risk profile influence circulating Angptl2 levels is unknown. We tested whether biliopancreatic diversion with duodenal switch (BPD-DS) surgery alters plasma Angptl2 concentrations. METHODS Severely obese patients (n = 73; body mass index: 49.8 ± 7.1) underwent BPD-DS. Plasma levels of Angptl2 and metabolic biomarkers were obtained acutely (days 1 and 5) and at 6 and 12 months after surgery, and compared with results in an age- and sex-matched control group (n = 33) remaining on the waiting list. RESULTS Preoperative Angptl2 levels were high (median: 12.3 ng/mL) and correlated with metabolic and anthropometric parameters. A significant (P < 0.01) increase in Angptl2 levels, fasting glucose, insulin, and interleukin-6 levels was observed acutely postoperatively (day 1) followed by a progressive decline from day 5. Besides weight loss, Angptl2 levels were decreased at the 12-month follow-up (11.5 ± 4.7 vs 14.0 ± 4.0 ng/mL, P < 0.0001), but not at the 6-month time point. Long-term changes in plasma Angptl2 levels showed significant positive correlations with changes in fasting glucose, insulin resistance, and tumour necrosis factor-α levels, and negative correlation with changes in leptin concentration (P < 0.05). No significant correlation was observed between changes in anthropometric parameters and Angptl2. CONCLUSIONS Plasma Angptl2 levels decreased after BPD-DS in severely obese patients; no changes occurred in control participants. Lowered circulating levels of the inflammatory factor Angptl2 because of BPD-DS were closely related to favourable changes in glucose-insulin homeostasis and inflammatory profiles.
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Affiliation(s)
- Marie-Eve Piché
- Quebec Heart and Lung Institute, Quebec City, Quebec, Canada; Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
| | - Nathalie Thorin-Trescases
- Montreal Heart Institute, Faculty of Medicine, Department of Surgery, University of Montreal, Montreal, Quebec, Canada
| | - Audrey Auclair
- Quebec Heart and Lung Institute, Quebec City, Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada
| | - Simon Marceau
- Quebec Heart and Lung Institute, Quebec City, Quebec, Canada; Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
| | - Julie Martin
- Quebec Heart and Lung Institute, Quebec City, Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada
| | - Annik Fortier
- Montreal Health Innovations Coordinating Center, Montreal, Quebec, Canada
| | - Eric Thorin
- Montreal Heart Institute, Faculty of Medicine, Department of Surgery, University of Montreal, Montreal, Quebec, Canada
| | - Paul Poirier
- Quebec Heart and Lung Institute, Quebec City, Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada.
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Zhang Y, Lu S, Li R. Association between Maternal Serum Concentrations of Angiopoietin-like Protein 2 in Early Pregnancy and Subsequent Risk of Gestational Diabetes Mellitus. Chin Med J (Engl) 2017; 129:2308-12. [PMID: 27647189 PMCID: PMC5040016 DOI: 10.4103/0366-6999.190662] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Background: A recent study reported a positive association between elevated serum levels of angiopoietin-like protein 2 (ANGPTL2) and the development of type 2 diabetes in a general population. However, the relationship of serum ANGPTL2 levels with the risk of developing gestational diabetes mellitus (GDM) has not been reported to date. The aim of this study was to investigate the change of maternal serum ANGPTL2 concentrations in the first trimester of pregnancy and to determine whether ANGPTL2 is a biomarker for subsequent GDM development. Methods: We conducted a prospective, nested case-control study in a pregnancy cohort. First-trimester ANGPTL2 levels were measured using a high-resolution assay in 89 women who subsequently developed GDM and in a random sample of 177 women who remained euglycemic throughout the pregnancy. Median ANGPTL2 levels were compared using Mann-Whitney U-test. Logistic regression was used to compute unadjusted and multivariable-adjusted odds ratios for developing GDM among ANGPTL2 quartiles. Results: The serum levels of ANGPTL2 was higher in women with GDM than that in women without GDM (3.06 [2.59, 3.65] ng/ml vs. 2.46 [2.05, 2.96] ng/ml, P = 0.003). Fasting blood glucose was higher in women with GDM than that in women without GDM (5.0 ± 0.9 mmol/L vs. 4.4 ± 0.6 mmol/L, P < 0.001). Glucose challenge test showed that the blood glucose was higher in women with GDM than that in women without GDM (9.1 ± 3.5 mmol/L vs. 6.2 ± 1.2 mmol/L, P < 0.001). A multivariate model adjusted for baseline characteristics, medical complications, and gestational characteristics revealed that the risk of developing GDM among women in Q4 compared with Q1 was 2.90-fold more likely to develop GDM later in pregnancy. Conclusions: At 11–13 weeks in pregnancies that develop GDM, the serum concentration of ANGPTL2 is increased, and it can be combined with maternal factors to provide effective early screening for GDM.
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Affiliation(s)
- Yan Zhang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
| | - Shan Lu
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
| | - Rong Li
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
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Sheng WZ, Chen YS, Tu CT, He J, Zhang B, Gao WD. ANGPTL2 expression in gastric cancer tissues and cells and its biological behavior. World J Gastroenterol 2016; 22:10364-10370. [PMID: 28058016 PMCID: PMC5175248 DOI: 10.3748/wjg.v22.i47.10364] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 08/25/2016] [Accepted: 09/14/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To explore expression of angiopoietin-like protein 2 (ANGPTL2) and its effect on biological behavior such as proliferation and invasiveness in gastric cancer.
METHODS Western blotting was used to detect expression of ANGPTL2 in 60 human normal gastric tissues, 60 human gastric cancer tissues and gastric cell lines including GES-1, N87, SGC7901, BGC823 and PAMC82. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Transwell assay were used to detect the proliferation and invasive ability of gastric cancer cells.
RESULTS Compared to normal tissues, ANGPTL2 protein levels were significantly upregulated in gastric tissues, and this level was closely correlated with gastric tumor grade, clinical stage and lymph node metastasis. Compared to GES-1 cells, ANGPTL2 mRNA and protein levels were significantly increased in gastric cancer cells including N87, SGC7901, BGC823 and PAMC82. The expression of ANGPTL2 in highly malignant gastric cancer cell lines BGC823 and PAMC82 was significantly higher than in low malignancy gastric cancer cell lines N87 and SGC7901. MTT and Transwell experiments indicated that the proliferation rate and invasive ability of stable overexpressed gastric cancer cells was faster than in cells transfected with Lv-NC and blank control cells, and the invasive ability of stable overexpressed gastric cancer cells was higher than that of cells transfected with Lv-NC and blank control cells.
CONCLUSION ANGPTL2 contributed to proliferation and invasion of gastric cancer cells. In clinical treatment, ANGPTL2 may become a new target for treatment of gastric cancer.
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Gellen B, Thorin-Trescases N, Sosner P, Gand E, Saulnier PJ, Ragot S, Fraty M, Laugier S, Ducrocq G, Montaigne D, Llaty P, Rigalleau V, Zaoui P, Halimi JM, Roussel R, Thorin E, Hadjadj S. ANGPTL2 is associated with an increased risk of cardiovascular events and death in diabetic patients. Diabetologia 2016; 59:2321-2330. [PMID: 27491833 DOI: 10.1007/s00125-016-4066-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 07/12/2016] [Indexed: 01/24/2023]
Abstract
AIMS/HYPOTHESIS A high serum angiopoietin-like 2 (ANGPTL2) concentration is an independent risk factor for developing diabetes and is associated with insulin resistance and atherosclerosis. In this work, we have examined the impact of serum ANGPTL2 on improving cardiovascular (CV) risk stratification in patients with type 2 diabetes. METHODS A prospective, monocentric cohort of consecutive type 2 diabetes patients (the SURDIAGENE cohort; total of 1353 type 2 diabetes patients; 58% men, mean ± SD age 64 ± 11 years) was followed for a median of 6.0 years for death as primary endpoint and major adverse CV events (MACE; i.e. CV death, myocardial infarction or stroke) as a secondary endpoint. Patients with end-stage renal disease, defined as a requirement for dialysis or a history of kidney transplantation, were excluded. Patients were grouped into quartiles according to ANGPTL2 concentrations at inclusion: <11.2 (Q1), 11.2-14.7 (Q2), 14.8-19.5 (Q3) or >19.5 (Q4) ng/ml. RESULTS During follow up, 367 patients (representing 4.5% of the total person-years) died and 290 patients (representing 3.7% of the total person-years) presented with MACE. Both the survival and MACE-free survival rates were significantly different between ANGPTL2 quartiles (logrank 82.12, p < 0.0001 for death; and logrank 65.14, p < 0.0001 for MACE). Patients with ANGPTL2 concentrations higher than 19.5 ng/ml (Q4) had a significantly higher risk of death and MACE than those with ANGPTL2 levels of 19.5 ng/ml or less (Q1-3) (HR for death 2.44 [95% CI 1.98, 3.00], p < 0.0001; HR for MACE 2.43 [95% CI 1.92, 3.06], p < 0.0001) after adjustment for sex, age and established CV risk factors. Using ANGPTL2 concentrations, prediction of the risk of mortality, as assessed by integrated discrimination improvement (IDI), was significantly improved (IDI 0.006 ± 0.002, p = 0.0002). CONCLUSIONS/INTERPRETATION In patients with type 2 diabetes, serum ANGPTL2 concentrations were independently associated with death and MACE. Therefore, ANGPTL2 is a promising candidate biomarker for improving risk stratification in type 2 diabetes patients, and may prove to be a valuable therapeutic target.
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Affiliation(s)
- Barnabas Gellen
- ELSAN, Polyclinique de Poitiers, 1 Rue de la Providence, F-8600, Poitiers, France.
- Department of Cardiology, CHU Henri Mondor, Créteil, France.
- Faculté de Médecine et Pharmacie, Université de Poitiers, Poitiers, France.
| | - Nathalie Thorin-Trescases
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal Heart Institute, Montreal, QC, Canada
| | - Philippe Sosner
- CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France
- Université de Poitiers, Laboratoire MOVE (EA 6314), Poitiers, France
- Centre Médico-Sportif Mon Stade, Paris, France
| | - Elise Gand
- CHU de Poitiers, Pôle Dune, Poitiers, France
| | - Pierre-Jean Saulnier
- CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France
- Inserm, CIC 1402, Poitiers, France
- UFR Médecine Pharmacie, Université de Poitiers, Poitiers, France
| | - Stéphanie Ragot
- CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France
| | | | - Stéphanie Laugier
- UFR Médecine Pharmacie, Université de Poitiers, Poitiers, France
- Endocrinologie-Diabétologie, CHU de Poitiers, Poitiers, France
| | - Grégory Ducrocq
- Département Hospitalo-Universitaire FIRE, APHP, Hôpital Bichat, Paris, France
- Faculté de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Inserm U-1148, Paris, France
| | - David Montaigne
- CHU Lille, Service d'Explorations Fonctionnelles Cardiovasculaires, Hôpital Cardiologique, Lille, France
- Faculté de Médecine, Université de Lille, Lille, France
- Inserm U1011, Lille, France
- EGID, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Pierre Llaty
- CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France
| | - Vincent Rigalleau
- CHU Bordeaux, Haut-Lévêque Hospital, Nutrition-Diabetology Department, Pessac, France
| | - Philippe Zaoui
- CHU de Grenoble, Service Néphrologie, Dialyse et Transplantation, Grenoble, France
- Faculté de Médecine, Université Joseph Fournier, Grenoble, France
| | - Jean-Michel Halimi
- CHU de Tours, Service Néphrologie, Dialyse et Transplantation, Tours, France
| | - Ronan Roussel
- Département Hospitalo-Universitaire FIRE, APHP, Hôpital Bichat, Paris, France
- Faculté de Médecine, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Eric Thorin
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal Heart Institute, Montreal, QC, Canada
| | - Samy Hadjadj
- CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France
- Inserm, CIC 1402, Poitiers, France
- UFR Médecine Pharmacie, Université de Poitiers, Poitiers, France
- Endocrinologie-Diabétologie, CHU de Poitiers, Poitiers, France
- Inserm U1082, Poitiers, France
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Thorin-Trescases N, Hayami D, Yu C, Luo X, Nguyen A, Larouche JF, Lalongé J, Henri C, Arsenault A, Gayda M, Juneau M, Lambert J, Thorin E, Nigam A. Exercise Lowers Plasma Angiopoietin-Like 2 in Men with Post-Acute Coronary Syndrome. PLoS One 2016; 11:e0164598. [PMID: 27736966 PMCID: PMC5063321 DOI: 10.1371/journal.pone.0164598] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 09/27/2016] [Indexed: 12/11/2022] Open
Abstract
Pro-inflammatory angiopoietin-like 2 (angptl2) promotes endothelial dysfunction in mice and circulating angptl2 is higher in patients with cardiovascular diseases. We previously reported that a single bout of physical exercise was able to reduce angptl2 levels in coronary patients. We hypothesized that chronic exercise would reduce angptl2 in patients with post-acute coronary syndrome (ACS) and endothelial dysfunction. Post-ACS patients (n = 40, 10 women) were enrolled in a 3-month exercise-based prevention program. Plasma angptl2, hs-CRP, and endothelial function assessed by scintigraphic forearm blood flow, were measured before and at the end of the study. Exercise increased VO2peak by 10% (p<0.05), but did not significantly affect endothelial function, in both men and women. In contrast, exercise reduced angptl2 levels only in men (-26±7%, p<0.05), but unexpectedly not in women (+30±16%), despite similar initial levels in both groups. Exercise reduced hs-CRP levels in men but not in women. In men, levels of angptl2, but not of hs-CRP, reached at the end of the training program were negatively correlated with VO2peak (r = -0.462, p = 0.012) and with endothelial function (r = -0.419, p = 0.033) measured at baseline: better initial cardiopulmonary fitness and endothelial function correlated with lower angptl2 levels after exercise. Pre-exercise angptl2 levels were lower if left ventricular ejection time was long (p<0.05) and the drop in angptl2 induced by exercise was greater if the cardiac output was high (p<0.05). In conclusion, in post-ACS men, angptl2 levels are sensitive to chronic exercise training. Low circulating angptl2 reached after training may reflect good endothelial and cardiopulmonary functions.
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Affiliation(s)
| | - Doug Hayami
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
- Cardiac Rehabilitation and Prevention Center (EPIC) of the Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
| | - Carol Yu
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
- Departments of Pharmacology and Surgery, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Xiaoyan Luo
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
| | - Albert Nguyen
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
- Departments of Pharmacology and Surgery, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Jean-François Larouche
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
- Cardiac Rehabilitation and Prevention Center (EPIC) of the Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
| | - Julie Lalongé
- Cardiac Rehabilitation and Prevention Center (EPIC) of the Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
| | - Christine Henri
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
| | - André Arsenault
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
- Montreal Behavioral Medicine Centre, Montreal, Quebec, Canada
| | - Mathieu Gayda
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
- Cardiac Rehabilitation and Prevention Center (EPIC) of the Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
| | - Martin Juneau
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
- Cardiac Rehabilitation and Prevention Center (EPIC) of the Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
| | - Jean Lambert
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
- School of Public Health, University of Montreal, Montreal, Quebec, Canada
| | - Eric Thorin
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
- Departments of Pharmacology and Surgery, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
- * E-mail:
| | - Anil Nigam
- Montreal Heart Institute, Research Center, University of Montreal, Montreal, Quebec, Canada
- Cardiac Rehabilitation and Prevention Center (EPIC) of the Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
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ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism. Nat Commun 2016; 7:13016. [PMID: 27677409 PMCID: PMC5052800 DOI: 10.1038/ncomms13016] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 08/25/2016] [Indexed: 12/21/2022] Open
Abstract
A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. When that response is excessive, pathological cardiac remodelling occurs, which can progress to heart failure, a leading cause of death worldwide. Mechanisms underlying this response are not fully understood. Here, we report that expression of angiopoietin-like protein 2 (ANGPTL2) increases in pathologically-remodeled hearts of mice and humans, while decreased cardiac ANGPTL2 expression occurs in physiological cardiac remodelling induced by endurance training in mice. Mice overexpressing ANGPTL2 in heart show cardiac dysfunction caused by both inactivation of AKT and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a signalling and decreased myocardial energy metabolism. Conversely, Angptl2 knockout mice exhibit increased left ventricular contractility and upregulated AKT-SERCA2a signalling and energy metabolism. Finally, ANGPTL2-knockdown in mice subjected to pressure overload ameliorates cardiac dysfunction. Overall, these studies suggest that therapeutic ANGPTL2 suppression could antagonize development of heart failure. Heart responds to increased workload by enlarging cardiomyocytes to preserve function, but in pathologies hypertrophy leads to heart failure. Here the authors show that ANGPTL2 activity in the heart is critical for determining beneficial vs. pathological hypertrophy via its effect on AKT-SERCA2a signaling and myocardial energy.
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Hata J, Mukai N, Nagata M, Ohara T, Yoshida D, Kishimoto H, Shibata M, Hirakawa Y, Endo M, Ago T, Kitazono T, Oike Y, Kiyohara Y, Ninomiya T. Serum Angiopoietin–Like Protein 2 Is a Novel Risk Factor for Cardiovascular Disease in the Community. Arterioscler Thromb Vasc Biol 2016; 36:1686-91. [DOI: 10.1161/atvbaha.116.307291] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 06/15/2016] [Indexed: 01/29/2023]
Abstract
Objective—
Angiopoietin-like protein 2 (ANGPTL2), a proinflammatory mediator, has been reported to accelerate the development of insulin resistance, endothelial dysfunction, and atherosclerosis in mice. However, no cohort studies have examined the relationship between serum ANGPTL2 levels and the development of cardiovascular disease (CVD) in a general population.
Approach and Results—
A total of 3005 community-dwelling Japanese aged ≥40 years without a history of CVD were divided into 4 groups according to the quartiles of serum ANGPTL2 concentrations (Q1, lowest and Q4, highest) and followed up for 10 years. The hazards ratios and their 95% confidence intervals for the development of CVD (coronary heart disease or stroke) were estimated using a Cox proportional hazards model. During the follow-up, 219 first-ever CVD events were observed. The risk of CVD increased significantly with elevating ANGPTL2 levels after adjustment for age, sex, serum total cholesterol, use of lipid-lowering agents, ECG abnormalities, smoking habits, alcohol intake, and regular exercise (hazards ratios [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.27 [0.80–2.04]; Q3, 1.48 [0.95–2.32]; and Q4, 1.85 [1.20–2.85];
P
=0.003 for trend). After additional adjustment for metabolic syndrome components and serum high-sensitivity C-reactive protein levels as an inflammatory marker, the association was attenuated but remained significant (hazards ratios [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.21 [0.76–1.94]; Q3, 1.38 [0.87–2.17]; and Q4, 1.66 [1.05–2.60];
P
=0.02 for trend).
Conclusions—
Our findings suggest that elevated serum ANGPTL2 levels are a novel risk factor for the development of CVD in the general population. This association is partially mediated by metabolic disorders and inflammation.
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Affiliation(s)
- Jun Hata
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Naoko Mukai
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Masaharu Nagata
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Tomoyuki Ohara
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Daigo Yoshida
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Hiro Kishimoto
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Mao Shibata
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Yoichiro Hirakawa
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Motoyoshi Endo
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Tetsuro Ago
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Takanari Kitazono
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Yuichi Oike
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Yutaka Kiyohara
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
| | - Toshiharu Ninomiya
- From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.)
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46
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Liu Z, Liu C, Hao C, Xue Q, Huang X, Zhang N, Bao H, Qu Q. Aberrant expression of angiopoietin-like proteins 1 and 2 in cumulus cells is potentially associated with impaired oocyte developmental competence in polycystic ovary syndrome. Gynecol Endocrinol 2016; 32:557-61. [PMID: 26829602 DOI: 10.3109/09513590.2016.1138463] [Citation(s) in RCA: 9] [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] [Indexed: 11/13/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder associated with obesity, insulin resistance, hyperandrogenism, alterations in ovarian angiogenesis and impaired oocyte competence. Emerging evidence demonstrates that angiopoietin-like protein 1 (ANGPTL1) and angiopoietin-like protein 2 (ANGPTL2) have an important influence on angiogenesis, androgen biosynthesis, insulin resistance and adipocytes function. In this study, we set out to determine the potential relationship between ANGPTL1, ANGPTL2 and oocyte competence in PCOS through analyzing the expression levels and dynamic pattern of the two genes in cumulus cells (CCs) during different phases of nuclear maturation of PCOS patients and control groups undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization and embryo transfer. We found that the relative abundance of ANGPTL1 and ANGPTL2 transcripts in CCs from patients with PCOS showed dynamic changes during oocyte maturation. Specifically, their expressions were increased significantly at the Metaphase II stage. In summary, the present novel evidence indicates that the expression patterns of ANGPTL1 and ANGPTL2 mRNAs are disordered during oocyte maturation in PCOS, which were potentially related to aberrant oocyte quality and developmental potency, at least in part, via pathological angiogenesis and metabolism.
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Affiliation(s)
- Zhenteng Liu
- a Department of Reproductive Medicine , Yantai Yuhuangding Hospital, Affiliated Hospital of Medical College of Qingdao University , Yantai , Shandong , China
| | - Chang Liu
- b Medical College of Shandong University , Jinan , Shandong , China , and
| | - Cuifang Hao
- a Department of Reproductive Medicine , Yantai Yuhuangding Hospital, Affiliated Hospital of Medical College of Qingdao University , Yantai , Shandong , China
| | - Qianwen Xue
- c Department of Gynecology , Qingdao Women and Children Health Care Center , Qingdao , Shandong , China
| | - Xin Huang
- a Department of Reproductive Medicine , Yantai Yuhuangding Hospital, Affiliated Hospital of Medical College of Qingdao University , Yantai , Shandong , China
| | - Ning Zhang
- a Department of Reproductive Medicine , Yantai Yuhuangding Hospital, Affiliated Hospital of Medical College of Qingdao University , Yantai , Shandong , China
| | - Hongchu Bao
- a Department of Reproductive Medicine , Yantai Yuhuangding Hospital, Affiliated Hospital of Medical College of Qingdao University , Yantai , Shandong , China
| | - Qinglan Qu
- a Department of Reproductive Medicine , Yantai Yuhuangding Hospital, Affiliated Hospital of Medical College of Qingdao University , Yantai , Shandong , China
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47
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Nguyen A, Mamarbachi M, Turcot V, Lessard S, Yu C, Luo X, Lalongé J, Hayami D, Gayda M, Juneau M, Thorin-Trescases N, Lettre G, Nigam A, Thorin E. Lower Methylation of the ANGPTL2 Gene in Leukocytes from Post-Acute Coronary Syndrome Patients. PLoS One 2016; 11:e0153920. [PMID: 27101308 PMCID: PMC4839636 DOI: 10.1371/journal.pone.0153920] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 04/06/2016] [Indexed: 02/08/2023] Open
Abstract
DNA methylation is believed to regulate gene expression during adulthood in response to the constant changes in environment. The methylome is therefore proposed to be a biomarker of health through age. ANGPTL2 is a circulating pro-inflammatory protein that increases with age and prematurely in patients with coronary artery diseases; integrating the methylation pattern of the promoter may help differentiate age- vs. disease-related change in its expression. We believe that in a pro-inflammatory environment, ANGPTL2 is differentially methylated, regulating ANGPTL2 expression. To test this hypothesis we investigated the changes in promoter methylation of ANGPTL2 gene in leukocytes from patients suffering from post-acute coronary syndrome (ACS). DNA was extracted from circulating leukocytes of post-ACS patients with cardiovascular risk factors and from healthy young and age-matched controls. Methylation sites (CpGs) found in the ANGPTL2 gene were targeted for specific DNA methylation quantification. The functionality of ANGPTL2 methylation was assessed by an in vitro luciferase assay. In post-ACS patients, C-reactive protein and ANGPTL2 circulating levels increased significantly when compared to healthy controls. Decreased methylation of specific CpGs were found in the promoter of ANGPTL2 and allowed to discriminate age vs. disease associated methylation. In vitro DNA methylation of specific CpG lead to inhibition of ANGPTL2 promoter activity. Reduced leukocyte DNA methylation in the promoter region of ANGPTL2 is associated with the pro-inflammatory environment that characterizes patients with post-ACS differently from age-matched healthy controls. Methylation of different CpGs in ANGPTL2 gene may prove to be a reliable biomarker of coronary disease.
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Affiliation(s)
- Albert Nguyen
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
- Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Maya Mamarbachi
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
| | - Valérie Turcot
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
| | - Samuel Lessard
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
| | - Carol Yu
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
- Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Xiaoyan Luo
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
| | - Julie Lalongé
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
- Cardiac Rehabilitation and Prevention Center (EPIC) of the Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Doug Hayami
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
- Cardiac Rehabilitation and Prevention Center (EPIC) of the Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Mathieu Gayda
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
- Cardiac Rehabilitation and Prevention Center (EPIC) of the Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Martin Juneau
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
- Cardiac Rehabilitation and Prevention Center (EPIC) of the Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | | | - Guillaume Lettre
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Anil Nigam
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
- Cardiac Rehabilitation and Prevention Center (EPIC) of the Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
- * E-mail: (AN); (ET)
| | - Eric Thorin
- Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
- * E-mail: (AN); (ET)
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48
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Hirasawa M, Takubo K, Osada H, Miyake S, Toda E, Endo M, Umezawa K, Tsubota K, Oike Y, Ozawa Y. Angiopoietin-like Protein 2 Is a Multistep Regulator of Inflammatory Neovascularization in a Murine Model of Age-related Macular Degeneration. J Biol Chem 2016; 291:7373-85. [PMID: 26839315 PMCID: PMC4817169 DOI: 10.1074/jbc.m115.710186] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Indexed: 01/19/2023] Open
Abstract
Choroidal neovascularization (CNV) is a pathogenic process of age-related macular degeneration, a vision-threatening disease. The retinal pigment epithelium and macrophages both influence CNV development. However, the underlying mechanisms remain obscure. Here, we focus on Angptl2 (angiopoietin-like protein 2), a cytokine involved in age-related systemic diseases. Angptl2 was originally identified as an adipocytokine and is also expressed in the eye. Using a laser-induced CNV model, we found thatAngptl2KO mice exhibited suppressed CNV development with reduced macrophage recruitment and inflammatory mediator induction. The mediators monocyte chemotactic protein-1, interleukin-1β (Il-1β),Il-6, matrix metalloprotease-9 (Mmp-9), and transforming growth factor-β1 (Tgf-β1) that were up-regulated during CNV development were all suppressed in the retinal pigment epithelium-choroid of CNV models generated in theAngptl2KO mice. Bone marrow transplantation using wild-type and KO mice suggested that both bone marrow-derived and host-derived Angptl2 were responsible for macrophage recruitment and CNV development. Peritoneal macrophages derived fromAngptl2KO mice expressed lower levels of the inflammatory mediators. In the wild-type peritoneal macrophages and RAW264.7 cells, Angptl2 induced the mediators via integrins α4 and β2, followed by the downstream activation of NF-κB and ERK. The activation of NF-κB and ERK by Angptl2 also promoted macrophage migration. Therefore, Angptl2 from focal tissue might trigger macrophage recruitment, and that from recruited macrophages might promote expression of inflammatory mediators including Angptl2 in an autocrine and/or paracrine fashion to facilitate CNV development. Angptl2 might therefore represent a multistep regulator of CNV pathogenesis and serve as a new therapeutic target for age-related macular degeneration.
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Affiliation(s)
- Manabu Hirasawa
- From the Laboratory of Retinal Cell Biology and the Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan, the Department of Ophthalmology, Tokyo Dental College Suidobashi Hospital, Tokyo 101-0061 Japan
| | - Keiyo Takubo
- the Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | | | | | - Eriko Toda
- From the Laboratory of Retinal Cell Biology and
| | - Motoyoshi Endo
- the Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8555, Japan
| | - Kazuo Umezawa
- the Department of Molecular Target Medicine Screening, Aichi Medical University School of Medicine, Aichi, 480-1195, Japan
| | - Kazuo Tsubota
- the Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yuichi Oike
- the Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8555, Japan, the Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan, and
| | - Yoko Ozawa
- From the Laboratory of Retinal Cell Biology and the Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan,
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Shimomura M, Oyama JI, Takeuchi M, Shibata Y, Yamamoto Y, Kawasaki T, Komoda H, Kodama K, Sakuma M, Toyoda S, Inoue Y, Mine D, Natsuaki M, Komatsu A, Hikichi Y, Yamagishi SI, Inoue T, Node K. Acute effects of statin on reduction of angiopoietin-like 2 and glyceraldehyde-derived advanced glycation end-products levels in patients with acute myocardial infarction: a message from SAMIT (Statin for Acute Myocardial Infarction Trial). Heart Vessels 2015; 31:1583-9. [PMID: 26699899 DOI: 10.1007/s00380-015-0773-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 11/20/2015] [Indexed: 11/29/2022]
Abstract
Experimental ischemia-reperfusion models have shown that 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, have cardioprotective effects. SAMIT (Statin Acute Myocardial Infarction Trial) is a multicenter prospective open randomized trial, designed to evaluate the effects of statin treatment from the earliest stage on cardioprotection in patients with acute myocardial infarction (AMI). Patients were randomly assigned to receive atorvastatin (initial dose of 40 mg at admission followed by the maintenance dose of 10 mg/day for 30 days) or not (control), and then immediately underwent percutaneous coronary intervention (PCI) for the culprit lesion. The primary endpoints were infarct size and left ventricular function. The secondary endpoints were major adverse cardiac and cerebrovascular events (MACCE) and various biomarkers. There were no significant differences in baseline characteristics between 2 groups of the statin treatment group and the control group. The left ventricular ejection fraction increased at 6 months after the onset of AMI, compared with the baseline level in the atorvastatin group (P < 0.05), while it did not change in the control group. Although there were no significant differences in the MACCE, the changes in the levels of angiopoietin-like protein 2 (ANGPTL2) (P < 0.05), and glyceraldehyde-derived advanced glycation end-products, (TAGE) (P < 0.01) were suppressed at 2 weeks in the atorvastatin group, compared with the control group. Statin therapy started early after the onset reduced the levels of ANGPTL2 and TAGE, and thus, might have cardioprotective effects in patients with AMI.
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Affiliation(s)
- Mitsuhiro Shimomura
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Jun-Ichi Oyama
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
| | - Masayoshi Takeuchi
- Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan
| | - Yoshisato Shibata
- Department of Cardiology, Miyazaki Medical Association Hospital, Miyazaki, Japan
| | - Yusuke Yamamoto
- Division of Cardiology, Cardiovascular and Aortic Center, Saiseikai Fukuoka General Hospital, Fukuoka, Japan
| | | | - Hiroshi Komoda
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Kazuhisa Kodama
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Masashi Sakuma
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Shigeru Toyoda
- Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Yohei Inoue
- Department of Cardiology, Miyazaki Medical Association Hospital, Miyazaki, Japan
| | - Daigo Mine
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Masahiro Natsuaki
- Division of Cardiology, Cardiovascular and Aortic Center, Saiseikai Fukuoka General Hospital, Fukuoka, Japan
| | - Aiko Komatsu
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Yutaka Hikichi
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Sho-Ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Fukuoka, Japan
| | - Teruo Inoue
- Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan
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50
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Wensveen FM, Valentić S, Šestan M, Wensveen TT, Polić B. Interactions between adipose tissue and the immune system in health and malnutrition. Semin Immunol 2015; 27:322-33. [PMID: 26603491 DOI: 10.1016/j.smim.2015.10.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 10/26/2015] [Accepted: 10/27/2015] [Indexed: 02/07/2023]
Abstract
Adipose tissue provides the body with a storage depot of nutrients that is drained during times of starvation and replenished when food sources are abundant. As such, it is the primary sensor for nutrient availability in the milieu of an organism, which it communicates to the body through the excretion of hormones. Adipose tissue regulates a multitude of body functions associated with metabolism, such as gluconeogenesis, feeding and nutrient uptake. The immune system forms a vital layer of protection against micro-organisms that try to gain access to the nutrients contained in the body. Because infections need to be resolved as quickly as possible, speed is favored over energy-efficiency in an immune response. Especially when immune cells are activated, they switch to fast, but energy-inefficient anaerobic respiration to fulfill their energetic needs. Despite the necessity for an effective immune system, it is not given free rein in its energy expenditure. Signals derived from adipose tissue limit immune cell numbers and activity under conditions of nutrient shortage, whereas they allow proper immune cell activity when food sources are sufficiently available. When excessive fat accumulation occurs, such as in diet-induced obesity, adipose tissue becomes the site of pathological immune cell activation, causing chronic low-grade systemic inflammation. Obesity is therefore associated with a number of disorders in which the immune system plays a central role, such as atherosclerosis and non-alcoholic steatohepatitis. In this review, we will discuss the way in which adipose tissue regulates activity of the immune system under healthy and pathological conditions.
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Affiliation(s)
- Felix M Wensveen
- Department of Histology & Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia; Department of Experimental Immunology, Amsterdam Medical Centre, Amsterdam, The Netherlands
| | - Sonja Valentić
- Department of Histology & Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Marko Šestan
- Department of Histology & Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | | | - Bojan Polić
- Department of Histology & Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
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