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Menounos S, Shen H, Tipirneni S, Bhaskar SMM. Decoding the Nexus: Cellular and Molecular Mechanisms Linking Stroke and Neurotoxic Microenvironments in Brain Cancer Patients. Biomolecules 2024; 14:1507. [PMID: 39766214 PMCID: PMC11673144 DOI: 10.3390/biom14121507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 11/23/2024] [Accepted: 11/25/2024] [Indexed: 01/06/2025] Open
Abstract
Stroke is an often underrecognized albeit significant complication in patients with brain cancer, arising from the intricate interplay between cancer biology and cerebrovascular health. This review delves into the multifactorial pathophysiological framework linking brain cancer to elevated stroke risk, with particular emphasis on the crucial role of the neurotoxic microenvironment (NTME). The NTME, characterized by oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, creates a milieu that promotes and sustains vascular and neuronal injury. Key pathogenic factors driving brain cancer-related stroke include cancer-related hypercoagulability, inflammatory and immunological mechanisms, and other tumor-associated processes, including direct tumor compression, infection-related sequelae, and treatment-related complications. Recent advances in genomic and proteomic profiling present promising opportunities for personalized medicine, enabling the identification of biomarkers-such as oncogenes and tumor suppressor genes-that predict stroke susceptibility and inform individualized therapeutic strategies. Targeting the NTME through antioxidants to alleviate oxidative stress, anti-inflammatory agents to mitigate neuroinflammation, and therapies aimed at reinforcing the BBB could pave the way for more effective stroke prevention and management strategies. This integrative approach holds the potential to reduce both the incidence and severity of stroke, ultimately improving clinical outcomes and quality of life for brain cancer patients. Further research and well-designed clinical trials are essential to validate these strategies and integrate them into routine clinical practice, thereby redefining the management of stroke risk in brain cancer patients.
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Affiliation(s)
- Spiro Menounos
- Global Health Neurology Lab, Sydney, NSW 2150, Australia; (S.M.); (H.S.); (S.T.)
- School of Clinical Medicine, Medicine & Health, University of New South Wales (UNSW), St George and Sutherland Clinical Campuses, Sydney, NSW 2150, Australia
| | - Helen Shen
- Global Health Neurology Lab, Sydney, NSW 2150, Australia; (S.M.); (H.S.); (S.T.)
- UNSW Medicine and Health, University of New South Wales (UNSW), South West Sydney Clinical Campuses, Sydney, NSW 2170, Australia
| | - Shraddha Tipirneni
- Global Health Neurology Lab, Sydney, NSW 2150, Australia; (S.M.); (H.S.); (S.T.)
- UNSW Medicine and Health, University of New South Wales (UNSW), South West Sydney Clinical Campuses, Sydney, NSW 2170, Australia
| | - Sonu M. M. Bhaskar
- Global Health Neurology Lab, Sydney, NSW 2150, Australia; (S.M.); (H.S.); (S.T.)
- UNSW Medicine and Health, University of New South Wales (UNSW), South West Sydney Clinical Campuses, Sydney, NSW 2170, Australia
- NSW Brain Clot Bank, NSW Health Pathology, Sydney, NSW 2170, Australia
- Ingham Institute for Applied Medical Research, Clinical Sciences Stream, Liverpool, NSW 2170, Australia
- Department of Neurology & Neurophysiology, Liverpool Hospital and South West Sydney Local Health District, Liverpool, NSW 2150, Australia
- National Cerebral and Cardiovascular Center (NCVC), Department of Neurology, Division of Cerebrovascular Medicine and Neurology, Suita 564-8565, Osaka, Japan
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Wang X, Cao L, Liu S, Zhou Y, Zhou J, Zhao W, Gao S, Liu R, Shi Y, Shao C, Fang J. The critical roles of IGFs in immune modulation and inflammation. Cytokine 2024; 183:156750. [PMID: 39243567 DOI: 10.1016/j.cyto.2024.156750] [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: 06/03/2024] [Revised: 07/31/2024] [Accepted: 09/03/2024] [Indexed: 09/09/2024]
Abstract
Insulin-like growth factors (IGFs) are crucial for embryonic and postnatal growth and development, influencing cell survival, metabolism, myogenesis, and cancer progression. Many studies have demonstrated that IGFs also play prominent roles in the modulation of both innate and adaptive immune systems during inflammation. Strikingly, IGFs dictate the phenotype and functional properties of macrophages and T cells. Furthermore, the interplay between IGFs and inflammatory cytokines may generate tissue-protective properties during inflammation. Herein, we review the recent advances on the dialogue between immune cells and IGFs, especially zooming in on the significance of immunomodulatory properties in inflammatory conditions, cancer and autoimmune diseases. The investigation of IGFs may have broad clinical implications.
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Affiliation(s)
- Xin Wang
- The Third/Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Lijuan Cao
- The Third/Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China; Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome "Tor Vergata", Rome, Italy
| | - Shisong Liu
- The Third/Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yipeng Zhou
- The Third/Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Jiarui Zhou
- The Third/Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Wenxuan Zhao
- The Third/Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Shengqi Gao
- The Third/Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Rui Liu
- The Third/Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China; Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome "Tor Vergata", Rome, Italy
| | - Yufang Shi
- The Third/Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China; Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Changshun Shao
- The Third/Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China.
| | - Jiankai Fang
- The Third/Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China.
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Yu J, Yang J, He Q, Zhang Z, Xu G. Comprehensive bioinformatics analysis reveals the crosstalk genes and immune relationship between the systemic lupus erythematosus and venous thromboembolism. Front Immunol 2023; 14:1196064. [PMID: 37465678 PMCID: PMC10350530 DOI: 10.3389/fimmu.2023.1196064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 05/30/2023] [Indexed: 07/20/2023] Open
Abstract
Background It is well known that patients with systemic lupus erythematosus (SLE) had a high risk of venous thromboembolism (VTE). This study aimed to identify the crosstalk genes between SLE and VTE and explored their clinical value and molecular mechanism initially. Methods We downloaded microarray datasets of SLE and VTE from the Gene Expression Omnibus (GEO) dataset. Differential expression analysis was applied to identify the crosstalk genes (CGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the shared genes. The shared diagnostic biomarkers of the two diseases were further screened from CGs using least absolute shrinkage and selection operator (Lasso) regression. Two risk scores for SLE and VTE were constructed separately to predict the likelihood of illness according to the diagnostic biomarkers using a logical regression algorithm. The immune infiltration levels of SEL and VTE were estimated via the CIBERSORT algorithm and the relationship of CGs with immune cell infiltration was investigated. Finally, we explored potential phenotype subgroups in SLE and VTE based on the expression level of CGs through the consensus clustering method and studied immune cell infiltration in different subtypes. Result A total of 171 CGs were obtained by the intersection of differentially expressed genes (DEGs) between SLE and VTE cohorts. The functional enrichment shown these CGs were mainly related to immune pathways. After screening by lasso regression, we found that three hub CGs (RSAD2, HSP90AB1, and FPR2) were the optimal shared diagnostic biomarkers for SLE and VTE. Based on the expression level of RSAD2 and HSP90AB1, two risk prediction models for SLE and VTE were built by multifactor logistic regression and systemically validated in internal and external validation datasets. The immune infiltration results revealed that CGs were highly correlated with multiple infiltrated immunocytes. Consensus clustering was used to respectively regroup SLE and VTE patients into C1 and C2 clusters based on the CGs expression profile. The levels of immune cell infiltration and immune activation were higher in C1 than in C2 subtypes. Conclusion In our study, we further screen out diagnostic biomarkers from crosstalk genes SLE and VTE and built two risk scores. Our findings reveal a close relationship between CGs and the immune microenvironment of diseases. This provides clues for further exploring the common mechanism and interaction between the two diseases.
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Affiliation(s)
- Jingfan Yu
- Department of Vascular Surgery and Intervention, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Jian Yang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Qifan He
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhixuan Zhang
- Department of Vascular Surgery and Intervention, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Guoxiong Xu
- Department of Vascular Surgery and Intervention, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
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Bickel MA, Csik B, Gulej R, Ungvari A, Nyul-Toth A, Conley SM. Cell non-autonomous regulation of cerebrovascular aging processes by the somatotropic axis. Front Endocrinol (Lausanne) 2023; 14:1087053. [PMID: 36755922 PMCID: PMC9900125 DOI: 10.3389/fendo.2023.1087053] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/04/2023] [Indexed: 01/24/2023] Open
Abstract
Age-related cerebrovascular pathologies, ranging from cerebromicrovascular functional and structural alterations to large vessel atherosclerosis, promote the genesis of vascular cognitive impairment and dementia (VCID) and exacerbate Alzheimer's disease. Recent advances in geroscience, including results from studies on heterochronic parabiosis models, reinforce the hypothesis that cell non-autonomous mechanisms play a key role in regulating cerebrovascular aging processes. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) exert multifaceted vasoprotective effects and production of both hormones is significantly reduced in aging. This brief overview focuses on the role of age-related GH/IGF-1 deficiency in the development of cerebrovascular pathologies and VCID. It explores the mechanistic links among alterations in the somatotropic axis, specific macrovascular and microvascular pathologies (including capillary rarefaction, microhemorrhages, impaired endothelial regulation of cerebral blood flow, disruption of the blood brain barrier, decreased neurovascular coupling, and atherogenesis) and cognitive impairment. Improved understanding of cell non-autonomous mechanisms of vascular aging is crucial to identify targets for intervention to promote cerebrovascular and brain health in older adults.
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Affiliation(s)
- Marisa A. Bickel
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Boglarka Csik
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Rafal Gulej
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Anna Ungvari
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- International Training Program in Geroscience, Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Adam Nyul-Toth
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- International Training Program in Geroscience, Department of Public Health, Semmelweis University, Budapest, Hungary
- Institute of Biophysics, Biological Research Centre, Eötvös Lorand Research Network (ELKH), Szeged, Hungary
| | - Shannon M. Conley
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
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Sun MY, Bhaskar SMM. When Two Maladies Meet: Disease Burden and Pathophysiology of Stroke in Cancer. Int J Mol Sci 2022; 23:15769. [PMID: 36555410 PMCID: PMC9779017 DOI: 10.3390/ijms232415769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/08/2022] [Accepted: 12/10/2022] [Indexed: 12/15/2022] Open
Abstract
Stroke and cancer are disabling diseases with an enormous global burden, disproportionately affecting vulnerable populations and low- and middle-income countries. Both these diseases share common risk factors, which warrant concerted attention toward reshaping population health approaches and the conducting of fundamental studies. In this article, an overview of epidemiological trends in the prevalence and burden of cancer and stroke, underlying biological mechanisms and clinical risk factors, and various tools available for risk prediction and prognosis are provided. Finally, future recommendations for research and existing gaps in our understanding of pathophysiology. Further research must investigate the causes that predispose patients to an increased risk of stroke and/or cancer, as well as biomarkers that can be used to predict growing morbidity and mortality.
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Affiliation(s)
- Ming-Yee Sun
- Global Health Neurology Lab, Sydney, NSW 2000, Australia
- Neurovascular Imaging Laboratory, Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia
- UNSW Medicine and Health, University of New South Wales (UNSW), South Western Sydney Clinical Campuses, Sydney, NSW 2170, Australia
| | - Sonu M. M. Bhaskar
- Global Health Neurology Lab, Sydney, NSW 2000, Australia
- Neurovascular Imaging Laboratory, Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia
- Department of Neurology & Neurophysiology, Liverpool Hospital and South West Sydney Local Health District (SWSLHD), Liverpool, NSW 2170, Australia
- NSW Brain Clot Bank, NSW Health Pathology, Sydney, NSW 2170, Australia
- Stroke & Neurology Research Group, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia
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Charalambous C, Moon JC, Holly JMP, Chaturvedi N, Hughes AD, Captur G. Declining Levels and Bioavailability of IGF-I in Cardiovascular Aging Associate With QT Prolongation-Results From the 1946 British Birth Cohort. Front Cardiovasc Med 2022; 9:863988. [PMID: 35528832 PMCID: PMC9072634 DOI: 10.3389/fcvm.2022.863988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/21/2022] [Indexed: 11/30/2022] Open
Abstract
Background As people age, circulating levels of insulin-like growth factors (IGFs) and IGF binding protein 3 (IGFBP-3) decline. In rat cardiomyocytes, IGF-I has been shown to regulate sarcolemmal potassium channel activity and late sodium current thus impacting cardiac repolarization and the heart rate-corrected QT (QTc). However, the relationship between IGFs and IGFBP-3 with the QTc interval in humans, is unknown. Objectives To examine the association of IGFs and IGFBP-3 with QTc interval in an older age population-based cohort. Methods Participants were from the 1946 Medical Research Council (MRC) National Survey of Health and Development (NSHD) British birth cohort. Biomarkers from blood samples at age 53 and 60-64 years (y, exposures) included IGF-I/II, IGFBP-3, IGF-I/IGFBP-3 ratio and the change (Δ) in marker levels between the 60-64 and 53y sampled timepoints. QTc (outcome) was recorded from electrocardiograms at the 60-64y timepoint. Generalized linear multivariable models with adjustments for relevant demographic and clinical factors, were used for complete-cases and repeated after multiple imputation. Results One thousand four hundred forty-eight participants were included (48.3% men; QTc mean 414 ms interquartile range 26 ms). Univariate analysis revealed an association between low IGF-I and IGF-I/IGFBP-3 ratio at 60-64y with QTc prolongation [respectively: β -0.30 ms/nmol/L, (95% confidence intervals -0.44, -0.17), p < 0.001; β-28.9 ms/unit (-41.93, -15.50), p < 0.001], but not with IGF-II or IGFBP-3. No association with QTc was found for IGF biomarkers sampled at 53y, however both ΔIGF-I and ΔIGF-I/IGFBP-3 ratio were negatively associated with QTc [β -0.04 ms/nmol/L (-0.08, -0.008), p = 0.019; β -2.44 ms/unit (-4.17, -0.67), p = 0.007] while ΔIGF-II and ΔIGFBP-3 showed no association. In fully adjusted complete case and imputed models (reporting latter) low IGF-I and IGF-I/IGFBP-3 ratio at 60-64y [β -0.21 ms/nmol/L (-0.39, -0.04), p = 0.017; β -20.14 ms/unit (-36.28, -3.99), p = 0.015], steeper decline in ΔIGF-I [β -0.05 ms/nmol/L/10 years (-0.10, -0.002), p = 0.042] and shallower rise in ΔIGF-I/IGFBP-3 ratio over a decade [β -2.16 ms/unit/10 years (-4.23, -0.09), p = 0.041], were all independently associated with QTc prolongation. Independent associations with QTc were also confirmed for other previously known covariates: female sex [β 9.65 ms (6.65, 12.65), p < 0.001], increased left ventricular mass [β 0.04 ms/g (0.02, 0.06), p < 0.001] and blood potassium levels [β -5.70 ms/mmol/L (-10.23, -1.18) p = 0.014]. Conclusion Over a decade, in an older age population-based cohort, declining levels and bioavailability of IGF-I associate with prolongation of the QTc interval. As QTc prolongation associates with increased risk for sudden death even in apparently healthy people, further research into the antiarrhythmic effects of IGF-I on cardiomyocytes is warranted.
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Affiliation(s)
- Christos Charalambous
- UCL MRC Unit for Lifelong Health and Ageing, University College London, London, United Kingdom
| | - James C Moon
- UCL Institute of Cardiovascular Science, University College London, London, United Kingdom
- Cardiac MRI Unit, Barts Heart Centre, London, United Kingdom
| | - Jeff M P Holly
- National Institute for Health Research (NIHR) Bristol Nutrition Biomedical Research Unit, Level 3, University Hospitals Bristol Education and Research Centre, Bristol, United Kingdom
- Faculty of Health Sciences, School of Translational Health Sciences, Bristol Medical School, Southmead Hospital, University of Bristol, Bristol, United Kingdom
| | - Nishi Chaturvedi
- UCL MRC Unit for Lifelong Health and Ageing, University College London, London, United Kingdom
| | - Alun D Hughes
- UCL MRC Unit for Lifelong Health and Ageing, University College London, London, United Kingdom
- UCL Institute of Cardiovascular Science, University College London, London, United Kingdom
| | - Gabriella Captur
- UCL MRC Unit for Lifelong Health and Ageing, University College London, London, United Kingdom
- UCL Institute of Cardiovascular Science, University College London, London, United Kingdom
- Cardiology Department, Centre for Inherited Heart Muscle Conditions, The Royal Free Hospital, London, United Kingdom
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La Valle A, Crocco M, Chiarenza DS, Maghnie M, d'Annunzio G. Endothelial impairment evaluation by peripheral arterial tonometry in pediatric endocrinopathies: A narrative review. World J Diabetes 2021; 12:810-826. [PMID: 34168730 PMCID: PMC8192248 DOI: 10.4239/wjd.v12.i6.810] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/30/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
Endothelial dysfunction (ED) is characterized by an imbalance between vasodilator and vasoconstriction agents. Several pathological conditions clinically diagnosed in childhood and adolescence are characterized by ED and increased risk for early development of microangiopathic and macroangiopathic impairment, in particular type 1 diabetes mellitus (T1DM), T2DM, obesity, metabolic syndromeand pituitary dysfunction associated to various endocrinopathies. More recently insulin resistance following chemotherapy or radiotherapy for tumors, bone marrow transplantation for hematological malignancies (i.e., cancer survivors), or immunosuppressive treatment for solid organ transplantation has been observed. Assessment of ED by means of non-invasive techniques is the gold standard for early ED detection before clinical manifestation. It is aimed to recognize patients at risk and to avoid the development and progression of more serious illnesses. Reactive hyperemia-peripheral artery tonometry is a noninvasive technique to assess peripheral endothelial function by measuring modifications in digital pulse volume during reactive hyperemia, and represents a non-invasive, reproducible and operator-independent tool able to detect precocious ED. This narrative review aimed to provide an overview of the most important papers regarding ED detection by EndoPat 2000 in children and adolescents with different endocrine diseases. A comprehensive search of English language articles was performed in the MEDLINE database without using other search filters except the publication interval between 2005 and 2020.
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Affiliation(s)
- Alberto La Valle
- Pediatric Clinic and Endocrinology, IRCCS Istituto Giannina Gaslini, Genoa16147, Italy
- Pediatric Clinic and Endocrinology, IRCCS Giannina Gaslini Institute, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa, Genoa16147, Italy
| | - Marco Crocco
- Pediatric Clinic and Endocrinology, IRCCS Istituto Giannina Gaslini, Genoa16147, Italy
- Pediatric Clinic and Endocrinology, IRCCS Giannina Gaslini Institute, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa, Genoa16147, Italy
| | - Decimo Silvio Chiarenza
- Pediatric Clinic and Endocrinology, IRCCS Istituto Giannina Gaslini, Genoa16147, Italy
- Pediatric Clinic and Endocrinology, IRCCS Giannina Gaslini Institute, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa, Genoa16147, Italy
| | - Mohamad Maghnie
- Pediatric Clinic and Endocrinology, IRCCS Istituto Giannina Gaslini, Genoa16147, Italy
- Pediatric Clinic and Endocrinology, IRCCS Giannina Gaslini Institute, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa, Genoa16147, Italy
| | - Giuseppe d'Annunzio
- Pediatric Clinic and Endocrinology, IRCCS Istituto Giannina Gaslini, Genoa16147, Italy
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Kul S, Caklili OT, Tutuncu Y, Ozcan FB, Aksu F, Baycan OF, Atici A, Bilgili UZ, Takir M, Caliskan M. Endothelial dysfunction in patients with acromegaly and It's association with Endocan. Growth Horm IGF Res 2021; 56:101362. [PMID: 33221710 DOI: 10.1016/j.ghir.2020.101362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/15/2020] [Accepted: 10/26/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE This study aims to assess endocan levels in patients with acromegaly who have active disease or disease in remission and to investigate a relation between endocan levels and endothelial dysfunction in these patients. DESIGN The study is a case-control study. Study was conducted at Istanbul Medeniyet University Goztepe Training and Research Hospital between 2013 and 2019. Patients who were older than 18 years with acromegaly diagnosis were recruited if they agreed to participate. Patients with uncontrolled diabetes (DM), hypertension (HT), hyperlipidemia, decompensated heart failure, immune or infectious diseases, moderate-severe valve disease and stage 3 or more advanced chronic kidney disease were excluded. There were 30 healthy control subjects who agreed to participate to the study. Patients with acromegaly were divided into two groups as: disease active patients and patients in remission. Serum endocan levels were measured with enzyme linked immunosorbent assay (ELISA) method endothelial function was assessed with flow mediated dilatation (FMD). RESULTS There were 85 patients included to the study. Twenty-three patients had active disease, 31 were in remission and 31 were healthy controls. FMD was higher in controls compared to patients in active disease and patients in remission (p < 0.001). There was no difference between patients with active disease for FMD and patients in remission (p = 0.088). There was statistically significant correlation between FMD and endocan and insulin like growth hormone-1 (IGF-1) levels of patients with acromegaly. As FMD increased endocan and IGF-1 decreased. A moderate negative relation between FMD and endocan was identified (p < 0.001, r:-0.409) as well as FMD and IGF-1 levels (p:0.011, r:-0.377). Along with endocan and IGF-1, DM, HT, sex, body mass index, age and uric acid were associated with changes in FMD. CONCLUSIONS Endocan levels and endothelial function measured with FMD have an inverse relationship. Endocan may prove to be a marker for endothelial dysfunction in acromegaly.
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Affiliation(s)
- Seref Kul
- Istanbul Medeniyet University Faculty of Medicine, Department of Cardiology, Istanbul, Turkey
| | - Ozge Telci Caklili
- Istanbul University, Istanbul Faculty of Medicine, Department of Endocrinology, Istanbul, Turkey.
| | - Yasemin Tutuncu
- Endocrinology and Metabolism Clinic, Haydarpaşa Education and Training Hospital, Istanbul, Turkey
| | - Fatma Betul Ozcan
- Istanbul Medeniyet University Faculty of Medicine, Department of Cardiology, Istanbul, Turkey
| | - Feyza Aksu
- Istanbul Medeniyet University Faculty of Medicine, Department of Cardiology, Istanbul, Turkey
| | - Omer Faruk Baycan
- Istanbul Medeniyet University Faculty of Medicine, Department of Cardiology, Istanbul, Turkey
| | - Adem Atici
- Istanbul Medeniyet University Faculty of Medicine, Department of Cardiology, Istanbul, Turkey
| | | | - Mumtaz Takir
- Istanbul Medeniyet University Faculty of Medicine, Department of Endocrinology and Metabolism, Istanbul, Turkey
| | - Mustafa Caliskan
- Istanbul Medeniyet University Faculty of Medicine, Department of Cardiology, Istanbul, Turkey
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Harada K, Hanayama Y, Obika M, Itoshima K, Okada K, Otsuka F. Clinical relevance of insulin-like growth factor-1 to cardiovascular risk markers. Aging Male 2020; 23:1030-1038. [PMID: 31446822 DOI: 10.1080/13685538.2019.1657083] [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] [Indexed: 10/26/2022] Open
Abstract
OBJECTIVE Insulin-like growth factor-1 (IGF-1) is an anabolic hormone, the levels of which decline with age. The present study aimed to determine the impact of age-related declines in serum IGF-1 levels on various physiological processes. DESIGN We retrospectively reviewed the medical records of patients whose serum IGF-1 levels were estimated in our department, and assessed the relationships between serum IGF-1 levels and various physiological parameters. RESULTS A total of 427 patients with a mean (± standard deviation) age of 52.8 (± 17.1) years were included in the analysis. The levels of serum IGF-1 showed significant positive correlation with those of hemoglobin and hematocrit, and negative correlation with the presence of inflammatory and fibrin-related markers including C-reactive protein (CRP) and procalcitonin (PCT), and D-dimer and fibrin degradation products (FDP). These tendencies persisted after exclusion of patients with pituitary disease. CONCLUSIONS In this study population of diverse diseases and backgrounds, a decline in serum IGF-1 levels with age was associated with an increase in inflammatory and fibrin-related markers. This may explain the correlation between low serum IGF-1 levels and an increased risk of cardiovascular events. Our findings suggest that serum IGF-1 is a clinically relevant marker of cardiovascular risk, particularly in males.
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Affiliation(s)
- Ko Harada
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshihisa Hanayama
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Mikako Obika
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Koichi Itoshima
- Department of Laboratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Ken Okada
- Department of Laboratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Fumio Otsuka
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Department of Laboratory Medicine, Okayama University Hospital, Okayama, Japan
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Obradovic M, Zafirovic S, Soskic S, Stanimirovic J, Trpkovic A, Jevremovic D, Isenovic ER. Effects of IGF-1 on the Cardiovascular System. Curr Pharm Des 2019; 25:3715-3725. [DOI: 10.2174/1381612825666191106091507] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/29/2019] [Indexed: 11/22/2022]
Abstract
:Cardiovascular (CV) diseases are the most common health problems worldwide, with a permanent increase in incidence. Growing evidence underlines that insulin-like growth factor 1 (IGF-1) is a very important hormone responsible for normal CV system physiology. IGF-1 is an anabolic growth hormone, responsible for cell growth, differentiation, proliferation, and survival. Despite systemic effects, IGF-1 exerts a wide array of influences in the CV system affecting metabolic homeostasis, vasorelaxation, cardiac contractility and hypertrophy, autophagy, apoptosis, and antioxidative processes. The vasodilatory effect of IGF-1, is achieved through the regulation of the activity of endothelial nitric oxide synthase (eNOS) and, at least partly, through enhancing inducible NOS (iNOS) activity. Also, IGF-1 stimulates vascular relaxation through regulation of sodium/potassiumadenosine- triphosphatase. Numerous animal studies provided evidence of diverse influences of IGF-1 in the CV system such as vasorelaxation, anti-apoptotic and prosurvival effects. Human studies indicate that low serum levels of free or total IGF-1 contribute to an increased risk of CV and cerebrovascular disease. Large human trials aiming at finding clinical efficacy and outcome of IGF-1-related therapy are of great interest.:We look forward to the development of new IGF 1 therapies with minor side effects. In this review, we discuss the latest literature data regarding the function of IGF-1 in the CV system in the physiological and pathophysiological conditions.
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Affiliation(s)
- Milan Obradovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Sonja Zafirovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Sanja Soskic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Julijana Stanimirovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Andreja Trpkovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Danimir Jevremovic
- Faculty of Stomatology, Pancevo, University Business Academy, 21000 Novi Sad, Serbia
| | - Esma R. Isenovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
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Chen L, He FJ, Dong Y, Huang Y, Harshfield GA, Zhu H. Sodium Reduction, Metabolomic Profiling, and Cardiovascular Disease Risk in Untreated Black Hypertensives. Hypertension 2019; 74:194-200. [PMID: 31079530 PMCID: PMC9116731 DOI: 10.1161/hypertensionaha.119.12880] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Dietary sodium restriction has multiple beneficial effects on cardiovascular health. The underlying mechanisms are not fully understood, and the roles of metabolomics have been rarely studied. We aimed to test the hypothesis that the reduction in dietary sodium intake would induce changes in metabolomic profiling among black hypertensives, and the changes would be associated with reduced blood pressure (BP) and improved skin capillary density. A total of 64 untreated black hypertensives were included from a randomized, double-blind, placebo-controlled cross-over trial of sodium reduction. The participants were given either 9 slow sodium tablets (10 mmol sodium per tablet) or placebo tablets daily for 6 weeks, they then crossed over to receive the other tablets for another 6 weeks, while on reduced sodium diet aiming at achieving daily sodium intake around 2.0 g. Untargeted metabolomic profiling was performed in paired serum samples, which were collected at the end of each period, so were BP and capillary density. Mixed-effects models were used. There were 34 metabolites identified with raw P's<0.05. Among those, 2 metabolites including β-hydroxyisovalerate and methionine sulfone were significantly increased with sodium reduction (false discovery rate =0.006 and 0.099, respectively). Increased β-hydroxyisovalerate was associated with reduced office systolic BP and ambulatory daytime systolic BP, whereas increased methionine sulfone was associated with reduced 24-hour diastolic BP, ambulatory nighttime diastolic BP, and increased skin capillary density. Our results suggest that dietary sodium reduction increases the circulating levels of β-hydroxyisovalerate and methionine sulfone. Further studies are warranted. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00152074.
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Affiliation(s)
- Li Chen
- From the Georgia Prevention Institute, Department of Population Health Sciences, Medical College of Georgia, Augusta University (L.C., Y.D., Y.H., G.A.H., H.Z.)
| | - Feng J He
- Center for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (F.J.H.)
| | - Yanbin Dong
- From the Georgia Prevention Institute, Department of Population Health Sciences, Medical College of Georgia, Augusta University (L.C., Y.D., Y.H., G.A.H., H.Z.)
| | - Ying Huang
- From the Georgia Prevention Institute, Department of Population Health Sciences, Medical College of Georgia, Augusta University (L.C., Y.D., Y.H., G.A.H., H.Z.)
| | - Gregory A Harshfield
- From the Georgia Prevention Institute, Department of Population Health Sciences, Medical College of Georgia, Augusta University (L.C., Y.D., Y.H., G.A.H., H.Z.)
| | - Haidong Zhu
- From the Georgia Prevention Institute, Department of Population Health Sciences, Medical College of Georgia, Augusta University (L.C., Y.D., Y.H., G.A.H., H.Z.)
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12
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Du X, Liu Y, Zhao C, Fang J, Wang X, Wei L. Changes of serum 25(OH) D3 and IGF-1 levels in patients with thyroid nodules. BMC Endocr Disord 2019; 19:48. [PMID: 31077177 PMCID: PMC6509827 DOI: 10.1186/s12902-019-0376-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 04/25/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The present study aimed to study the relationship between serum 25 hydroxyvitamin D3(25(OH)D3) and insulin-like growth factor-1 (IGF-1) and thyroid nodules. METHODS Two hundred eighty-nine cases with thyroid nodules and 109 health subjects (control group) who admitted to the Hebei General Hospital during June 2016 to December 2016 were included in the study. Basic clinical information (age, sex, thyroid function, liver and kidney function, hypertension history, etc.) of patients were collected. Serum 25(OH) D3 and Serum IGF-1 were detected by electrochemiluminescence and radioimmunoassay methods, respectively. The relationship between the above-mentioned factors and thyroid nodules was statistically analyzed. RESULTS Serum 25(OH)D3, IGF-1, fasting blood glucose (FBG), total cholesterol (TC), waist circumference (WC), total triiodothyronine (TT3), total thyroxine (TT4), hypertension history, and drinking history were significantly different between the nodules group and the control group (P < 0.05). Logistic regression analysis showed that there was a negative correlation between thyroid nodules and levels of 25(OH)D3, IGF-1, TT3, as well as a positive correlation with FBG, TC, TT4, and hypertension. There was a positive correlation between IGF-1 and serum 25(OH)D3 in thyroid nodules (P < 0.05). After correcting the aforementioned factors, high-level of serum 25(OH)D3 was significantly correlated with the decreased incidence of thyroid nodules. CONCLUSIONS The incidence of thyroid nodules is relatively lower in a high-level of serum 25(OH)D3, and serum 25(OH)D3 may be a direct protective factor for thyroid nodules. Serum IGF-1 can be one of the indirect protective factors for thyroid nodules as well.
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Affiliation(s)
- Xueqin Du
- Hebei Medical University, Shijiazhuang, 050017 Hebei China
| | - Yi Liu
- Hebei North University, Zhangjiakou, 075000 Hebei China
| | - Chunhui Zhao
- Department of Pediatrics, Shijiazhuang Fourth Hospital, Shijiazhuang, 050011 Hebei China
| | - Jingzhou Fang
- Hebei North University, Zhangjiakou, 075000 Hebei China
| | - Xiangna Wang
- Hebei North University, Zhangjiakou, 075000 Hebei China
| | - Limin Wei
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, 050051 Hebei China
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Barnard SA, Smith W, Mels CMC, Botha S, Schutte AE. Bioavailable IGF-1 is beneficially associated with biomarkers of endothelial function in young healthy adults: The African-PREDICT study. Growth Horm IGF Res 2018; 41:28-33. [PMID: 29936324 DOI: 10.1016/j.ghir.2018.06.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 06/01/2018] [Accepted: 06/10/2018] [Indexed: 10/14/2022]
Abstract
INTRODUCTION Low circulating levels of insulin-like growth factor-1 (IGF-1) are associated with endothelial dysfunction, subsequently leading to the development of cardiovascular disease. OBJECTIVE To better understand the early phases of vascular deterioration in a young, healthy population, we investigated, cross-sectionally, whether biomarkers of endothelial function (intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand factor antigen (vWFag)) are associated with IGF-1 in a healthy study population forming part of the larger African Prospective study on the Early Detection and Identification of Cardiovascular diseases and Hypertension (African-PREDICT). METHOD We included 825 black and white men and women (aged 20-30 years) and determined IGF-1, IGF binding protein-3 (IGFBP-3), ICAM-1, VCAM-1 and vWFag from blood samples. We also measured 24-h blood pressure and health behaviours namely waist circumference, accelerometery, cotinine and gamma glutamyl transferase. We used the IGF-1/IGFBP-3 M ratio as an estimate of bioavailable IGF-1. RESULTS In multivariable-adjusted regression analyses performed in the total group, VCAM-1 associated positively with IGFBP-3 (β = 0.21; p < .001) and negatively with IGF-1/IGFBP-3 (β = -0.18; p < .001). ICAM-1 showed a borderline negative association with IGF-1 (β = -0.09; p = .054) and IGF-1/IGFBP-3 (β = -0.08; p = .057). vWFag was not associated with IGF-1, IGFBP-3 or bioavailable IGF-1. CONCLUSION VCAM-1 is beneficially associated with IGF-1 in a young healthy cohort, independent of sex, ethnicity, blood pressure and health behaviours - thereby confirming the potential importance of bioavailable IGF-1 in early vascular endothelial protection.
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Affiliation(s)
- Sunelle A Barnard
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa.
| | - Wayne Smith
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa; MRC Research Unit for Hypertension and Cardiovascular disease, North-West University, Potchefstroom, South Africa.
| | - Catharina M C Mels
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa; MRC Research Unit for Hypertension and Cardiovascular disease, North-West University, Potchefstroom, South Africa.
| | - Shani Botha
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa; MRC Research Unit for Hypertension and Cardiovascular disease, North-West University, Potchefstroom, South Africa.
| | - Aletta E Schutte
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa; MRC Research Unit for Hypertension and Cardiovascular disease, North-West University, Potchefstroom, South Africa.
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14
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Tellatin S, Maffei P, Osto E, Dassie F, Famoso G, Montisci R, Martini C, Fallo F, Marra MP, Mioni R, Iliceto S, Vettor R, Tona F. Coronary microvascular dysfunction may be related to IGF-1 in acromegalic patients and can be restored by therapy. Atherosclerosis 2018; 269:100-105. [DOI: 10.1016/j.atherosclerosis.2017.12.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 11/25/2017] [Accepted: 12/12/2017] [Indexed: 10/18/2022]
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15
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Shuang T, Fu M, Yang G, Wu L, Wang R. The interaction of IGF-1/IGF-1R and hydrogen sulfide on the proliferation of mouse primary vascular smooth muscle cells. Biochem Pharmacol 2017; 149:143-152. [PMID: 29248598 DOI: 10.1016/j.bcp.2017.12.009] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 12/12/2017] [Indexed: 11/25/2022]
Abstract
Hydrogen sulfide (H2S) is mostly produced by cystathionine-gamma-lyase (CSE) in vascular system and it inhibits the proliferation of vascular smooth muscle cells (SMCs). Insulin-like growth factor-1 (IGF-1), via its receptor (IGF-1R), exerts multiple physiological and pathophysiological effects on the vasculature, including stimulating SMC proliferation and migration, and inhibiting SMC apoptosis. Since H2S and IGF-1/IGF-1R have opposite effects on SMC proliferation, it becomes imperative to better understand the interaction of these two signaling mechanisms on SMC proliferation. SMCs isolated from small mesenteric arteries of CSE knockout (KO) and wild-type (WT) mice were used in the present study. The effects of IGF-1 and H2S on SMC proliferation were evaluated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and bromodeoxyuridine (BrdU) assays. Protein expression was determined by western blot, and H2S-induced protein S-sulfhydration was assessed with a modified biotin switch assay. We found that IGF-1 dose-dependently increased the proliferation of both WT-SMCs and KO-SMCs, and this effect was more significant in KO-SMCs. Supplement of sodium hydrosulfide (NaHS) inhibited IGF-1-induced cell proliferation, while this effect was abolished by blocking IGF-1/IGF-1R signaling with picropodophyllin (PPP) or knocking out of the expression of IGF-1R. H2S significantly down-regulates the expression of IGF-1R, stimulates IGF-1R S-sulfhydration, and attenuates the binding of IGF-1 with IGF-1R. This study provides novel insight on the involvement of IGF-1/IGF-1R in H2S-inhibited SMC proliferation and suggests H2S-based innovative treatment strategies for proliferative cardiovascular diseases such as atherosclerosis.
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Affiliation(s)
- Tian Shuang
- Cardiovascular and Metabolic Research Unit, Laurentian University, Canada; School of Human Kinetics, Laurentian University, Canada; Department of Biology, Laurentian University, Canada; Health Sciences North Research Institute, Sudbury, Ontario, Canada
| | - Ming Fu
- Cardiovascular and Metabolic Research Unit, Laurentian University, Canada; School of Human Kinetics, Laurentian University, Canada; Health Sciences North Research Institute, Sudbury, Ontario, Canada
| | - Guangdong Yang
- Cardiovascular and Metabolic Research Unit, Laurentian University, Canada; Department of Chemistry and Biochemistry, Laurentian University, Ontario, Canada
| | - Lingyun Wu
- Cardiovascular and Metabolic Research Unit, Laurentian University, Canada; School of Human Kinetics, Laurentian University, Canada; Health Sciences North Research Institute, Sudbury, Ontario, Canada
| | - Rui Wang
- Cardiovascular and Metabolic Research Unit, Laurentian University, Canada; Department of Biology, Laurentian University, Canada.
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16
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Friedrich CC, Lin Y, Krannich A, Wu Y, Vacanti JP, Neville CM. Enhancing engineered vascular networks in vitro and in vivo: The effects of IGF1 on vascular development and durability. Cell Prolif 2017; 51. [PMID: 29110360 DOI: 10.1111/cpr.12387] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 07/21/2017] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES Creation of functional, durable vasculature remains an important goal within the field of regenerative medicine. Engineered biological vasculature has the potential to restore or improve human tissue function. We hypothesized that the pleotropic effects of insulin-like growth factor 1 (IGF1) would enhance the engineering of capillary-like vasculature. MATERIALS AND METHODS The impact of IGF1 upon vasculogenesis was examined in in vitro cultures for a period of up to 40 days and as subcutaneous implants within immunodeficient mice. Co-cultures of human umbilical vein endothelial cells and human bone marrow-derived mesenchymal stem cells in collagen-fibronectin hydrogels were supplemented with either recombinant IGF1 protein or genetically engineered cells to provide sustained IGF1. Morphometric analysis was performed on the vascular networks that formed in four concentrations of IGF1. RESULTS IGF1 supplementation significantly enhanced de novo vasculogenesis both in vitro and in vivo. Effects were long-term as they lasted the duration of the study period, and included network density, vessel length, and diameter. Bifurcation density was not affected. However, the highest concentrations of IGF1 tested were either ineffective or even deleterious. Sustained IGF1 delivery was required in vivo as the inclusion of recombinant IGF1 protein had minimal impact. CONCLUSION IGF1 supplementation can be used to produce neovasculature with significantly enhanced network density and durability. Its use is a promising methodology for engineering de novo vasculature to support regeneration of functional tissue.
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Affiliation(s)
- Claudia C Friedrich
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.,Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.,Department of Anesthesiology and Intensive Care Medicine, Campus Virchow Klinikum and Campus Charité Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Yunfeng Lin
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.,Department of Orthopaedics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, China
| | - Alexander Krannich
- Department of Biostatistics, Clinical Research Unit, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Yinan Wu
- Department of Biostatistics, Clinical Research Unit, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Joseph P Vacanti
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.,Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Craig M Neville
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.,Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.,Department of Orthopaedics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Mesaros C, Blair IA. Mass spectrometry-based approaches to targeted quantitative proteomics in cardiovascular disease. Clin Proteomics 2016; 13:20. [PMID: 27713681 PMCID: PMC5050566 DOI: 10.1186/s12014-016-9121-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 07/19/2016] [Indexed: 01/11/2023] Open
Abstract
Mass spectrometry-based proteomics methodology has become an important tool in elucidating some of the underlying mechanisms involved in cardiovascular disease. The present review provides details on selected important protein targets where highly selective and specific mass spectrometry-based approaches have led to important new findings and provided new mechanistic information. The role of six proteins involved in the etiology of cardiovascular disease (acetylated platelet cyclooxygenase-1, serum apolipoprotein A1, apolipoprotein C-III, serum C-reactive protein, serum high mobility group box-1 protein, insulin-like growth factor I) and their quantification has been discussed. There are an increasing number of examples where highly selective mass spectrometry-based quantification has provided new important data that could not be obtained with less labor intensive and cheaper immunoassay-based procedures. It is anticipated that these findings will lead to significant advances in a number of important issues related to the role of specific proteins in cardiovascular disease. The availability of a new generation of high-resolution high-sensitivity mass spectrometers will greatly facilitate these studies so that in the future it will be possible to analyze serum proteins of relevance to cardiovascular disease with levels of specificity and/or sensitivity that cannot be attained by immunoassay-based procedures.
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Affiliation(s)
- Clementina Mesaros
- Penn SRP Center and Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104 USA ; BluePen Biomarkers, 3401 Grays Ferry Avenue, Philadelphia, PA 19146-2799 USA
| | - Ian A Blair
- Penn SRP Center and Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104 USA ; BluePen Biomarkers, 3401 Grays Ferry Avenue, Philadelphia, PA 19146-2799 USA
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Koegelenberg ASE, Smith W, Schutte R, Schutte AE. IGF-1 and NT-proBNP in a black and white population: The SABPA study. Eur J Clin Invest 2016; 46:795-803. [PMID: 27455178 DOI: 10.1111/eci.12663] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 07/21/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Black populations exhibit lower concentrations of the cardioprotective peptide, insulin-like growth factor-1 (IGF-1), and are more prone to develop hypertensive heart disease than whites. We therefore determined whether lower IGF-1 in black individuals relates to a marker of cardiac overload and systolic dysfunction, namely N-terminal prohormone B-type natriuretic peptide (NT-proBNP). MATERIALS AND METHODS We included 160 black and 195 white nondiabetic South African men and women (aged 44·4 ± 9·81 years) and measured ambulatory blood pressure, NT-proBNP, IGF-1 and insulin-like growth factor-binding protein-3 (IGFBP-3). RESULTS Although the black group presented elevated ambulatory blood pressure accompanied by lower IGF-1 compared to the white group (all P < 0·001), we found similar NT-proBNP concentrations (P = 0·72). Furthermore, in blacks we found a link between NT-proBNP and systolic blood pressure (SBP) (R(2) = 0·37; β = 0·28; P < 0·001), but not with IGF-1. In the white group, NT-proBNP was inversely associated with IGF-1 (R(2) = 0·39; β = -0·22; P < 0·001) after adjusting for covariates and potential confounders. As IGF-1 is attenuated in diabetes, we added the initially excluded patients with diabetes (n = 38), and the aforementioned associations remained robust. CONCLUSION Contrary to the white group, we found no association between NT-proBNP and IGF-1 in black adults. Our findings suggest that SBP and other factors may play a greater contributory role in cardiac pathology in blacks.
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Affiliation(s)
- Anna S E Koegelenberg
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa
| | - Wayne Smith
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa
| | - Rudolph Schutte
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa.,Postgraduate Medical Institute, Faculty of Medical Science, Anglia Ruskin University, Chelmsford, UK
| | - Aletta E Schutte
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa.,MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa
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Schutte AE, Conti E, Mels CM, Smith W, Kruger R, Botha S, Gnessi L, Volpe M, Huisman HW. Attenuated IGF-1 predicts all-cause and cardiovascular mortality in a Black population: A five-year prospective study. Eur J Prev Cardiol 2016; 23:1690-1699. [PMID: 27450159 DOI: 10.1177/2047487316661436] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 07/07/2016] [Indexed: 11/15/2022]
Abstract
BACKGROUND Inconsistent findings are reported on whether insulin-like growth factor-1 (IGF-1) is protective or harmful in predicting hypertension, carotid wall thickness and mortality. We determined the five-year prognostic value of IGF-1 for these outcomes in a large Black population prone to hypertension and cardiovascular disease. DESIGN A longitudinal study as part of the PURE (Prospective Urban and Rural Epidemiology) study, North West Province, South Africa. METHODS We measured IGF-1 and IGF binding protein-3 (IGFBP-3) in 1038 HIV-uninfected participants (age range 32-94 years) and assessed blood pressure, carotid intima-media thickness and mortality. RESULTS Over five years 116 deaths occurred. Baseline IGF-1 was similar in survivors and non-survivors (p = 0.50), but tended to be higher in survivors upon adjustment for IGFBP-3 and covariates (p = 0.061). Normotensives and hypertensives (p = 0.072), and those with carotid intima-media thickness < 0.9 mm and ≥ 0.9 mm also displayed similar baseline IGF-1 (p = 0.55). Multivariable-adjusted Cox-regression indicated high IGF-1 predicting lower risk for all-cause mortality (hazard ratio 0.45; 0.23-0.88) and cardiovascular mortality (hazard ratio 0.26; 0.08-0.83) when also adjusting for IGFBP-3. When including normo- and hypertensives at baseline, high IGF-1 was related to normotension at follow-up (hazard ratio 0.68; 0.49-0.95). We found no association with carotid intima-media thickness (hazard ratio 0.59; 0.31-1.14). CONCLUSION In a Black South African population with low socio-economic status and harmful health behaviours, we found a protective independent association between IGF-1 and hypertension, cardiovascular and all-cause mortality, with no association with carotid wall thickness.
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Affiliation(s)
- Aletta E Schutte
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa Medical Research Council, Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa
| | - Elena Conti
- Department of Clinical and Molecular Medicine, University of Rome, Sapienza, Italy
| | - Catharina Mc Mels
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa
| | - Wayne Smith
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa
| | - Ruan Kruger
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa
| | - Shani Botha
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa
| | - Lucio Gnessi
- Department of Experimental Medicine, Pathophysiology and Endocrinology Unit, University of Rome, Sapienza, Italy
| | - Massimo Volpe
- Department of Clinical and Molecular Medicine, University of Rome, Sapienza, Italy IRCCS Neuromed, Pozzilli, Italy
| | - Hugo W Huisman
- Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa Medical Research Council, Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa
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Córdova C, Boullosa DA, Custódio MR, Quaglia LA, Santos SN, Freitas WM, Sposito AC, Nóbrega OT. Atheroprotective Properties of Serum IGF-1 in the Carotid and Coronary Territories and Beneficial Role on the Physical Fitness of the Oldest Old. J Gerontol A Biol Sci Med Sci 2015; 71:1281-8. [DOI: 10.1093/gerona/glv216] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 11/09/2015] [Indexed: 12/21/2022] Open
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Koegelenberg A, Schutte R, Smith W, Schutte A. Bioavailable IGF-1 and its relationship with endothelial damage in a bi-ethnic population: The SABPA study. Thromb Res 2015; 136:1007-12. [DOI: 10.1016/j.thromres.2015.08.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 08/06/2015] [Accepted: 08/29/2015] [Indexed: 11/26/2022]
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McCarty MF, DiNicolantonio JJ. An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly. AGE (DORDRECHT, NETHERLANDS) 2015; 37:96. [PMID: 26362762 PMCID: PMC5005830 DOI: 10.1007/s11357-015-9823-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 07/28/2015] [Indexed: 06/05/2023]
Abstract
Restricted dietary intakes of protein or essential amino acids tend to slow aging and boost lifespan in rodents, presumably because they downregulate IGF-I/Akt/mTORC1 signaling that acts as a pacesetter for aging and promotes cancer induction. A recent analysis of the National Health and Nutrition Examination Survey (NHANES) III cohort has revealed that relatively low protein intakes in mid-life (under 10 % of calories) are indeed associated with decreased subsequent risk for mortality. However, in those over 65 at baseline, such low protein intakes were associated with increased risk for mortality. This finding accords well with other epidemiology correlating relatively high protein intakes with lower risk for loss of lean mass and bone density in the elderly. Increased efficiency of protein translation reflecting increased leucine intake and consequent greater mTORC1 activity may play a role in this effect; however, at present there is little solid evidence that leucine supplementation provides important long-term benefits to the elderly. Aside from its potential pro-anabolic impact, higher dietary protein intakes may protect the elderly in another way-by providing increased amino acid substrate for synthesis of key protective factors. There is growing evidence, in both rodents and humans, that glutathione synthesis declines with increasing age, likely reflecting diminished function of Nrf2-dependent inductive mechanisms that boost expression of glutamate cysteine ligase (GCL), rate-limiting for glutathione synthesis. Intracellular glutathione blunts the negative impact of reactive oxygen species (ROS) on cell health and functions both by acting as an oxidant scavenger and by opposing the pro-inflammatory influence of hydrogen peroxide on cell signaling. Fortunately, since GCL's K m for cysteine is close to intracellular cysteine levels, increased intakes of cysteine-achieved from whole proteins or via supplementation with N-acetylcysteine (NAC)-can achieve a compensatory increase in glutathione synthesis, such that more youthful tissue levels of this compound can be restored. Supplementation with phase 2 inducers-such as lipoic acid-can likewise increase glutathione levels by promoting increased GCL expression. In aging humans and/or rodents, NAC supplementation has exerted favorable effects on vascular health, muscle strength, bone density, cell-mediated immunity, markers of systemic inflammation, preservation of cognitive function, progression of neurodegeneration, and the clinical course of influenza-effects which could be expected to lessen mortality and stave off frailty. Hence, greater cysteine availability may explain much of the favorable impact of higher protein intakes on mortality and frailty risk in the elderly, and joint supplementation with NAC and lipoic acid could be notably protective in the elderly, particularly in those who follow plant-based diets relatively low in protein. It is less clear whether the lower arginine intake associated with low-protein diets has an adverse impact on vascular health.
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Affiliation(s)
- Mark F McCarty
- Catalytic Longevity, 7831 Rush Rose Dr., Apt. 316, Carlsbad, CA, 92009, USA.
| | - James J DiNicolantonio
- Preventive Cardiology Department, St. Luke's Mid America Heart Institute, Kansas City, MO, USA.
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Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants. Biogerontology 2015; 17:109-27. [PMID: 26306600 PMCID: PMC4724477 DOI: 10.1007/s10522-015-9600-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 08/19/2015] [Indexed: 02/07/2023]
Abstract
Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from “bad” to “good”); (iii) gene–gene interaction; and (iv) gene–environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease “risk allele” can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.
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Jespersen CHB, Vestergaard KR, Schou M, Teisner B, Goetze JP, Iversen K. Pregnancy-associated plasma protein-A and the vulnerable plaque. Biomark Med 2015; 8:1033-47. [PMID: 25343675 DOI: 10.2217/bmm.14.53] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
For more than a decade, pregnancy-associated plasma protein-A (PAPP-A) has been examined for its relation to acute coronary syndrome (ACS) and the vulnerable plaque. This review summarizes the current knowledge of plasma PAPP-A in relation to nonpregnant individuals focusing on patients with ACS, discusses its use as a possible biomarker for diagnosis and prognosis in ACS, briefly describes the challenges in different assay technologies and describes the effect of heparin administration on PAPP-A concentrations in plasma.
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Sirbu A, Nicolae H, Martin S, Barbu C, Copaescu C, Florea S, Panea C, Fica S. IGF-1 and Insulin Resistance Are Major Determinants of Common Carotid Artery Thickness in Morbidly Obese Young Patients. Angiology 2015; 67:259-65. [DOI: 10.1177/0003319715586499] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
We assessed the relationship between insulin resistance, serum insulin-like growth factor 1 (IGF-1) levels, and common carotid intima–media thickness (CC-IMT) in morbidly obese young patients. A total of 249 patients (aged 37.9 ± 9.8 years, body mass index [BMI] 45.6 ± 8.3 kg/m2) were evaluated (metabolic tests, serum IGF-1 measurements, homeostasis model assessment—insulin resistance [HOMA-IR], and ultrasonographically assessed CC-IMT) in a research program for bariatric surgery candidates. After adjusting for age, gender, BMI, systolic blood pressure, uric acid, antihypertensive and lipid-lowering treatment, metabolic syndrome, and metabolic class, both HOMA-IR and IGF-1 z-score were significantly associated with CC-IMT. These results were confirmed in logistic regression analysis, in which age (β = 1.11, P = .001), gender (β = 3.19, P = .001), HOMA-IR (β = 1.221, P = .005), and IGF-1 z-score (β = 1.734, P = .009) were the only independent determinants of abnormal CC-IMT, presumably modulating the effect of the other risk factors included in the regression. Area under the receiver–operating characteristic curve for the model was 0.841 (confidence interval: 0.776-0.907; P < .001). In conclusion, in morbidly obese young adults, insulin resistance and IGF-1 z-score are significantly associated with CC-IMT, independent of other major cardiovascular risk factors.
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Affiliation(s)
- Anca Sirbu
- Endocrinology Department, Elias University Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Victor Babes Institute, Bucharest, Romania
| | - Horia Nicolae
- Neurology Department, Elias University Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Sorina Martin
- Endocrinology Department, Elias University Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Carmen Barbu
- Endocrinology Department, Elias University Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | | | - Suzana Florea
- Endocrinology Department, Elias University Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Cristina Panea
- Neurology Department, Elias University Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Simona Fica
- Endocrinology Department, Elias University Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Liu P, Kong F, Wang J, Lu Q, Xu H, Qi T, Meng J. Involvement of IGF-1 and MEOX2 in PI3K/Akt1/2 and ERK1/2 pathways mediated proliferation and differentiation of perivascular adipocytes. Exp Cell Res 2015; 331:82-96. [DOI: 10.1016/j.yexcr.2014.09.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 09/02/2014] [Accepted: 09/07/2014] [Indexed: 01/20/2023]
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Abstract
Endothelial cells line blood vessels and modulate vascular tone, thrombosis, inflammatory responses and new vessel formation. They are implicated in many disease processes including atherosclerosis and cancer. IGFs play a significant role in the physiology of endothelial cells by promoting migration, tube formation and production of the vasodilator nitric oxide. These actions are mediated by the IGF1 and IGF2/mannose 6-phosphate receptors and are modulated by a family of high-affinity IGF binding proteins. IGFs also increase the number and function of endothelial progenitor cells, which may contribute to protection from atherosclerosis. IGFs promote angiogenesis, and dysregulation of the IGF system may contribute to this process in cancer and eye diseases including retinopathy of prematurity and diabetic retinopathy. In some situations, IGF deficiency appears to contribute to endothelial dysfunction, whereas IGF may be deleterious in others. These differences may be due to tissue-specific endothelial cell phenotypes or IGFs having distinct roles in different phases of vascular disease. Further studies are therefore required to delineate the therapeutic potential of IGF system modulation in pathogenic processes.
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Affiliation(s)
- Leon A Bach
- Department of Medicine (Alfred)Monash University, Prahran 3181, AustraliaDepartment of Endocrinology and DiabetesAlfred Hospital, Commercial Road, Melbourne 3004, Australia Department of Medicine (Alfred)Monash University, Prahran 3181, AustraliaDepartment of Endocrinology and DiabetesAlfred Hospital, Commercial Road, Melbourne 3004, Australia
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Role of insulin-like growth factor 1 in stent thrombosis under effective dual antiplatelet therapy. ADVANCES IN INTERVENTIONAL CARDIOLOGY 2014; 10:242-9. [PMID: 25489317 PMCID: PMC4252321 DOI: 10.5114/pwki.2014.46765] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 04/19/2014] [Accepted: 04/28/2014] [Indexed: 11/29/2022] Open
Abstract
Introduction Accumulating evidence now indicates that insulin-like growth factors (IGF) and their regulatory proteins are growth promoters for arterial cells and mediators of cardiovascular diseases. Aim We hypothetised that IGF-1 levels could play a role in the development of stent thrombosis (ST), and aimed to investigate the associations between stent thrombosis under effective dual antiplatelet therapy and IGF-1 levels and other related factors such as disease severity and LV ejection fraction in patients undergoing coronary stent placement. Material and methods A total of 128 patients undergoing coronary stent implantation were included in the analysis. Seventy-seven patients experiencing ST in the first year after stent implantation were defined as the ST group. Fifty-one patients without ST at least 1 year after stent implantation were defined as the no-thrombosis (NT) group. The IGF-1 levels, Gensini scores, and other related factors were measured. Results The IGF-1 levels were significantly higher in the stent thrombosis group than in the no-thrombosis group (122.22 ±50.61 ng/ml vs. 99.52 ±46.81 ng/ml, respectively, p < 0.039). The left ventricle ejection fraction (LVEF) values were significantly lower (44.13 ±9.25% vs. 55.81 ±8.77%, p < 0.0001) and Gensini scores were significantly higher (63.74 ±26.54 vs. 48.87 ±23.7, p < 0.004) in the ST group than in the NT group, respectively. In the linear regression analysis, IGF-1, Gensini score, LVEF, total cholesterol, and triglycerides were found to be independent risk factors for ST. Conclusions This study revealed that the plasma IGF-1 levels, disease severity, were significantly higher and LVEF was lower in patients with ST. High IGF-1 levels may identify patients who are at increased risk for ST. Future trials are necessary to confirm these results.
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Karambataki M, Malousi A, Kouidou S. Risk-associated coding synonymous SNPs in type 2 diabetes and neurodegenerative diseases: genetic silence and the underrated association with splicing regulation and epigenetics. Mutat Res 2014; 770:85-93. [PMID: 25771874 DOI: 10.1016/j.mrfmmm.2014.09.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 09/15/2014] [Accepted: 09/16/2014] [Indexed: 06/04/2023]
Abstract
Single nucleotide polymorphisms (SNPs) are tentatively critical with regard to disease predisposition, but coding synonymous SNPs (sSNPs) are generally considered "neutral". Nevertheless, sSNPs in serine/arginine-rich (SR) and splice-site (SS) exonic splicing enhancers (ESEs) or in exonic CpG methylation targets, could be decisive for splicing, particularly in aging-related conditions, where mis-splicing is frequently observed. We presently identified 33 genes T2D-related and 28 related to neurodegenerative diseases, by investigating the impact of the corresponding coding sSNPs on splicing and using gene ontology data and computational tools. Potentially critical (prominent) sSNPs comply with the following criteria: changing the splicing potential of prominent SR-ESEs or of significant SS-ESEs by >1.5 units (Δscore), or formation/deletion of ESEs with maximum splicing score. We also noted the formation/disruption of CpGs (tentative methylation sites of epigenetic sSNPs). All disease association studies involving sSNPs are also reported. Only 21/670 coding SNPs, mostly epigenetic, reported in 33 T2D-related genes, were found to be prominent coding synonymous. No prominent sSNPs have been recorded in three key T2D-related genes (GCGR, PPARGC1A, IGF1). Similarly, 20/366 coding synonymous were identified in ND related genes, mostly epigenetic. Meta-analysis showed that 17 of the above prominent sSNPs were previously investigated in association with various pathological conditions. Three out of four sSNPs (all epigenetic) were associated with T2D and one with NDs (branch site sSNP). Five were associated with other or related pathological conditions. None of the four sSNPs introducing new ESEs was found to be disease-associated. sSNPs introducing smaller Δscore changes (<1.5) in key proteins (INSR, IRS1, DISC1) were also correlated to pathological conditions. This data reveals that genetic variation in splicing-regulatory and particularly CpG sites might be related to disease predisposition and that in-silico analysis is useful for identifying sSNPs, which might be falsely identified as silent or synonymous.
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Affiliation(s)
- M Karambataki
- Lab of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - A Malousi
- Lab of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - S Kouidou
- Lab of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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Insulin-like growth factor-1 and lipoprotein profile in cord blood of preterm small for gestational age infants. J Dev Orig Health Dis 2014; 4:507-12. [PMID: 24924229 DOI: 10.1017/s2040174413000408] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Low birth weight was associated with cardiometabolic diseases in adult age. Insulin-like growth factor-1 (IGF-1) has a crucial role in fetal growth and also associates with cardiometabolic risks in adults. Therefore, we elucidated the association between IGF-1 level and serum lipids in cord blood of preterm infants. The subjects were 41 consecutive, healthy preterm neonates (27 male, 14 female) born at <37-week gestational age, including 10 small for gestational age (SGA) infants (<10th percentile). IGF-1 levels and serum lipids were measured in cord blood, and high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC) and very low-density lipoprotein triglyceride (VLDLTG) levels were determined by HPLC method. SGA infants had lower IGF-1 (13.1 ± 5.3 ng/ml), total cholesterol (TC) (55.0 ± 14.8), LDLC (21.6 ± 8.3) and HDLC (26.3 ± 11.3) levels, and higher VLDLTG levels (19.0 ± 12.7 mg/dl) than in appropriate for gestational age (AGA) infants (53.6 ± 25.6, 83.4 ± 18.9, 36.6 ± 11.1, 38.5 ± 11.6, 8.1 ± 7.0, respectively). In simple regression analyses, log IGF-1 correlated positively with birth weight (r = 0.721, P < 0.001), TC (r = 0.636, P < 0.001), LDLC (r = 0.453, P = 0.006), and HDLC levels (r = 0.648, P < 0.001), and negatively with log TG (r = -0.484, P = 0.002) and log VLDL-TG (r = -0.393, P = 0.018). Multiple regression analyses demonstrated that IGF-1 was an independent predictor of TC, HDLC and TG levels after the gestational age and birth weight were taken into account. In preterm SGA infants, cord blood lipids profile altered with the concomitant decrease in IGF-1 level.
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Compromised bioavailable IGF-1 of black men relates favourably to ambulatory blood pressure: The SABPA study. Atherosclerosis 2014; 233:139-44. [DOI: 10.1016/j.atherosclerosis.2013.12.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 11/26/2013] [Accepted: 12/09/2013] [Indexed: 02/01/2023]
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Schutte AE, Volpe M, Tocci G, Conti E. Revisiting the relationship between blood pressure and insulin-like growth factor-1. Hypertension 2014; 63:1070-7. [PMID: 24566078 DOI: 10.1161/hypertensionaha.113.03057] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Conflicting evidence exists on the relationship between blood pressure (BP) and insulin-like growth factor-1 (IGF-1). We reviewed available articles and pooled extrapolated regression coefficients for the association between BP and total IGF-1 as reported in the literature and included additional data from 912 individuals from the general population. We identified 20 studies including 11 704 subjects. We also measured total IGF-1, insulin-like binding protein-3, and BP in 912 black and white men and women from South Africa (aged 20-70 years). When plotting positive and negative weighed regression coefficients (29 data points) against IGF-1, we found a significant positive relationship (r=0.31; P<0.001; n=11 704) intercepting the 0 point at 191 ng/mL IGF-1, suggesting an inverse BP/IGF-1 relationship in low IGF-1 conditions, and a positive relationship in overtly high IGF-1 conditions. In conclusion, our findings suggest that the relationship between BP and IGF-1 is dependent on, or related to, IGF-1 concentrations, as an expression of direct or reverse causality. Low IGF-1 bioavailability (associated with aging and vascular deterioration), resistance to IGF-1, and the complex interplay between IGF-1 and other vasoactive hormones could mask the vasoprotective functions of IGF-1 in cross-sectional studies or could modify their functions in prospective studies.
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Affiliation(s)
- Aletta Elisabeth Schutte
- Hypertension in Africa Research Team, North-West University, Hoffman St, Private Bag X6001, Potchefstroom 2520, South Africa.
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Endothelial Insulin-Like Growth Factor-1 Modulates Proliferation and Phenotype of Smooth Muscle Cells Induced by Low Shear Stress. Ann Biomed Eng 2013; 42:776-86. [DOI: 10.1007/s10439-013-0957-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Accepted: 11/29/2013] [Indexed: 11/30/2022]
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MicroRNA-133a regulates insulin-like growth factor-1 receptor expression and vascular smooth muscle cell proliferation in murine atherosclerosis. Atherosclerosis 2013; 232:171-9. [PMID: 24401233 DOI: 10.1016/j.atherosclerosis.2013.11.029] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 10/31/2013] [Accepted: 11/01/2013] [Indexed: 01/30/2023]
Abstract
OBJECTIVE MicroRNA-133a (miR-133a) and insulin-like growth factor-1 (IGF-1) are two different molecules known to regulate cardiovascular cell proliferation. This study tested whether miR-133a affects expression of IGF-1 receptor (IGF-1R) and proliferation of IGF-1-stimulated vascular smooth muscle cells (VSMC) in a murine model of atherosclerosis. METHODS AND RESULTS Expression of IGF-1R was analyzed by immuno-fluorescence and immuno-blotting, and miR-133a by qRT-PCR in the aortas of wild-type C57BL/6J (WT) and apolipoprotein-E deficient (ApoE(-/-)) mice. Compared to those in WT aortas, the IGF-1R and miR-133a levels were lower in ApoE(-/-) aortas. ApoE(-/-) VSMC grew slower than WT cells in the cultures with IGF-1-containing medium. MiR-133a-specific inhibitor decreased miR-133a, IGF-1R expression, IGF-1-stimulated VSMC growth in lipoprotein deficient media. By contrast, miR-133a precursor increased IGF-1R levels and promoted IGF-1-induced VSMC proliferation. In the luciferase-IGF-1R 3'UTR reporter system, the reporter luciferase activity was not inhibited in VSMC with miR-133a overexpression. IGF-1R mRNA half-life in ApoE(-/-) VSMC was shorter than that in WT VSMC. MiR-133a inhibitor reduced but precursor increased the mRNA half-life, although the effects appeared less striking in ApoE(-/-) VSMC than in WT cells. CONCLUSION MiR-133a serves as a stimulatory factor for IGF-1R expression through prolonging IGF-1R mRNA half-life. In atherosclerosis induced by ApoE deficiency, reduced miR-133a expression is associated with lower IGF-1R levels and suppressive VSMC growth. Administration of miR-133a precursor may potentiate IGF-1-stimulated VSMC survival and growth.
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Olaiya MT, Chiou HY, Jeng JS, Lien LM, Hsieh FI. Significantly increased risk of cardiovascular disease among patients with gallstone disease: a population-based cohort study. PLoS One 2013; 8:e76448. [PMID: 24098504 PMCID: PMC3789705 DOI: 10.1371/journal.pone.0076448] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Accepted: 08/26/2013] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE To investigate whether gallstone disease (GD) increases the risk of developing cardiovascular disease (CVD) in a large population-based cohort. METHODS A study population including 6,981 patients with GD was identified from The Taiwan National Health Insurance Research Database between 2004 and 2005. GD patients were defined as patients with principal discharge diagnoses of cholelithiasis using the ICD-9-CM code 574. 27,924 patients without GD were randomly selected and matched for age and gender. All patients were followed for 6 years or until diagnosis for CVD. Cox proportional hazards regression model was used to assess the risk of developing CVD with adjustment for age, gender and co-morbid conditions. RESULTS During the six years follow-up period, 935 patients with GD and 2,758 patients without GD developed CVD. Patients with GD had an elevated risk of CVD (HR, 1.32; 95% CI, 1.22-1.43) when compared with those without GD. Similar relationship was observed when CVD was categorized i.e. stroke (HR, 1.15; 95% CI, 1.01-1.32), coronary heart disease (HR, 1.42; 95% CI, 1.28-1.58) and heart failure (HR, 1.31; 95% CI, 1.00-1.73). When GD was classified according to the level of severity, using patients without GD as reference, the risks of CVD were elevated in patients with non-severe GD (HR, 1.34; 95% CI, 1.24-1.46) as well as those with severe GD (HR, 1.20, 95% CI, 1.02-1.40), after adjusting for age, gender and comorbidities. In age-stratified analysis, patients aged 18-40 years with GD were at higher risk of developing CVD (HR, 1.42; 95% CI, 1.09-1.84) than older GD patients. CONCLUSION This study found an increased risk of CVD in patients diagnosed with GD. The excess risk was particularly high in younger GD patients. Prevention of GD could help reduce the risk of developing CVD, and the better effect could be achieved for the younger age groups.
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Affiliation(s)
| | - Hung-Yi Chiou
- School of Public Health, Taipei Medical University, Taipei, Taiwan
| | - Jiann-Shing Jeng
- The Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Li-Ming Lien
- Department of Neurology, Shin Kong WHS Memorial Hospital, Taipei, Taiwan
| | - Fang-I Hsieh
- School of Public Health, Taipei Medical University, Taipei, Taiwan
- * E-mail:
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Insulin-like growth factor 1 opposes the effects of C-reactive protein on endothelial cell activation. Mol Cell Biochem 2013; 385:199-205. [DOI: 10.1007/s11010-013-1828-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 09/14/2013] [Indexed: 12/20/2022]
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Conti E, Romiti A, Musumeci MB, Passerini J, Zezza L, Mastromarino V, D'Antonio C, Marchetti P, Paneni F, Autore C, Volpe M. Arterial thrombotic events and acute coronary syndromes with cancer drugs: Are growth factors the missed link? Int J Cardiol 2013; 167:2421-9. [DOI: 10.1016/j.ijcard.2013.01.052] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Accepted: 01/18/2013] [Indexed: 12/21/2022]
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Frauenknecht V, Thiel S, Storm L, Meier N, Arnold M, Schmid JP, Saner H, Schroeder V. Plasma levels of mannan-binding lectin (MBL)-associated serine proteases (MASPs) and MBL-associated protein in cardio- and cerebrovascular diseases. Clin Exp Immunol 2013; 173:112-20. [PMID: 23607747 DOI: 10.1111/cei.12093] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/05/2013] [Indexed: 01/15/2023] Open
Abstract
Growing evidence suggests a prominent role of the complement system in the pathogenesis of cardio- and cerebrovascular diseases (CVD). Mannan-binding lectin-associated serine proteases (MASPs) MASP-1 and MASP-2 of the complement lectin pathway contribute to clot formation and may represent an important link between inflammation and thrombosis. MBL-associated protein MAp44 has shown cardioprotective effects in murine models. However, MAp44 has never been measured in patients with CVD and data on MASP levels in CVD are scarce. Our aim was to investigate for the first time plasma levels of MAp44 and MASP-1, -2, -3 concomitantly in patients with CVD. We performed a pilot study in 50 healthy volunteers, in stable coronary artery disease (CAD) patients with one-vessel (n = 51) or three-vessel disease (n = 53) and age-matched controls with normal coronary arteries (n = 53), 49 patients after myocardial infarction (MI) and 66 patients with acute ischaemic stroke. We measured MAp44 and MASP-1 levels by in-house time-resolved immunofluorometric assays. MASP-2 and MASP-3 levels were measured using commercial enzyme-linked immunosorbent assay kits. MASP-1 levels were highest in subacute MI patients and lowest in acute stroke patients. MASP-2 levels were lower in MI and stroke patients compared with controls and CAD patients. MASP-3 and MAp44 levels did not differ between groups. MASP or MAp44 levels were not associated with severity of disease. MASP and MAp44 levels were associated with cardiovascular risk factors including dyslipidaemia, obesity and hypertension. Our results suggest that MASP levels may be altered in vascular diseases. Larger studies are needed to confirm our results and elucidate the underlying mechanisms.
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Affiliation(s)
- V Frauenknecht
- University Clinic of Haematology, Haemostasis Research Laboratory, University Hospital and University of Bern, Switzerland
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39
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Conti E, Zezza L, Ralli E, Caserta D, Musumeci MB, Moscarini M, Autore C, Volpe M. Growth factors in preeclampsia: a vascular disease model. A failed vasodilation and angiogenic challenge from pregnancy onwards? Cytokine Growth Factor Rev 2013; 24:411-25. [PMID: 23800655 DOI: 10.1016/j.cytogfr.2013.05.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2013] [Revised: 04/30/2013] [Accepted: 05/21/2013] [Indexed: 12/25/2022]
Abstract
Preeclampsia is the major cause of maternofetal and neonatal morbi-mortality including intrauterine growth retardation, miscarriages and stillbirths. Inadequate vascular dilation and angiogenesis represent the crucial underlying defect of gravidic hypertension, denoting a failed response to the vasodilatory and pro-angiogenic challenge imposed by pregnancy, especially if multifetal. A similar pathogenesis appears involved in gestational diabetes. In this review we aimed to provide a hint on understanding the deeply involved angiogenic disorders which eventually culminate in utero-placental failure. The key players in these complex processes may be found in an intricate network of growth factors (GFs) and GF inhibitors, controlled by several vascular risk factors modulated by environment and genes, which eventually impact on early and late cardiovascular outcomes of mother and fetus.
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Affiliation(s)
- E Conti
- Cardiology, Clinical and Molecular Medicine Department, "Sapienza" University of Rome, Italy.
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40
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Abstract
Ageing is a process characterized by a progressive decline in cellular function, organismal fitness and increased risk of age-related diseases and death. Several hundred theories have attempted to explain this phenomenon. One of the most popular is the 'oxidative stress theory', originally termed the 'free radical theory'. The endocrine system seems to have a role in the modulation of oxidative stress; however, much less is known about the role that oxidative stress might have in the ageing of the endocrine system and the induction of age-related endocrine diseases. This Review outlines the interactions between hormones and oxidative metabolism and the potential effects of oxidative stress on ageing of endocrine organs. Many different mechanisms that link oxidative stress and ageing are discussed, all of which converge on the induction or regulation of inflammation. All these mechanisms, including cell senescence, mitochondrial dysfunction and microRNA dysregulation, as well as inflammation itself, could be targets of future studies aimed at clarifying the effects of oxidative stress on ageing of endocrine glands.
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Affiliation(s)
- Giovanni Vitale
- Department of Clinical Sciences and Community Health, University of Milan, Istituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, Italy
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41
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Lin HL, Ueng KC, Wang HL, Chen TP, Yang SF, Chu SC, Hsieh YS. The impact of IGF-I gene polymorphisms on coronary artery disease susceptibility. J Clin Lab Anal 2013; 27:162-9. [PMID: 23423640 DOI: 10.1002/jcla.21581] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2012] [Accepted: 01/07/2013] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Coronary artery disease (CAD) was the second leading cause of death for the past 3 years in Taiwan. The insulin-like growth factor (IGF) system is considered a new risk factor of CAD because investigations show that the levels and bioactivity of IGF-I and IGFBP-3 (where IGFBP is insulin-like growth factor-binding protein) may be involved in elevating the risk of CAD. This study investigated the relationships among IGF-I +1770, IGF-I +6093, and IGFBP-3 -202 genetic polymorphisms and CAD in the Taiwanese population. METHODS A total of 581 subjects, including 390 non-CAD controls and 191 patients with CAD, were recruited and the isolated DNA was subjected to real-time polymerase chain to evaluate the effects of these three polymorphic variants on CAD. RESULTS Our results showed a significant association between the IGF-I +1770 gene polymorphism and increased risk of CAD. Furthermore, CAD patients with a minimum of one mutant C allele, T/C or C/C, in IGF-I +1770 gene polymorphism had significantly high blood pressure including systolic blood pressure (SBP; P = 0.025) and diastolic blood pressure (DBP; P = 0.004), compared to CAD patients with T/T homozygotes. Moreover, CAD patients with a minimum of one mutant A allele, G/A or A/A, in the IGF-I +6093 gene polymorphism had a 1.695-fold elevated risk of congestive heart failure (CHF), compared to CAD patients with the G/G homozygote. CONCLUSIONS Polymorphism of IGF-I +1770 was associated with increased CAD risk. In CAD patients, the contributions of IGF-I +1770 and +6093 could be through the effect on blood pressure in CAD patients.
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Affiliation(s)
- Hsiu-Ling Lin
- Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
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42
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43
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Bitar MS, Al-Mulla F. ROS constitute a convergence nexus in the development of IGF1 resistance and impaired wound healing in a rat model of type 2 diabetes. Dis Model Mech 2012; 5:375-88. [PMID: 22362362 PMCID: PMC3339831 DOI: 10.1242/dmm.007872] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
An indolent non-healing wound and insulin and/or insulin-like growth factor (IGF1) resistance are cardinal features of diabetes, inflammation and hypercortisolemia. Little is known about why these phenomena occur in so many contexts. Do the various triggers that induce insulin and/or IGF1 resistance and retard wound healing act through a common mechanism? Cultured dermal fibroblasts from rats and full-thickness excisional wounds were used as models to test the premise that reactive oxygen species (ROS) play a causal role in the development of IGF1 resistance and impaired wound healing under different but pathophysiologically relevant clinical settings, including diabetes, dexamethasone-induced hypercortisolemia and TNFα-induced inflammation. In normal fibroblasts, IGF1 initiated a strong degree of phosphorylation of insulin receptor substrate 1 (IRS1) (Tyr612) and Akt (Ser473), concomitantly with increased PI3K activity. This phenomenon seemed to be attenuated in fibroblasts that had phenotypic features of diabetes, inflammation or hypercortisolemia. Notably, these cells also exhibited an increase in the activity of the ROS–phospho-JNK (p-JNK)–p-IRS1 (Ser307) axis. The above-mentioned defects were reflected functionally by attenuation in IGF1-dependent stimulation of key fibroblast functions, including collagen synthesis and cell proliferation, migration and contraction. The effects of IGF1 on glucose disposal and cutaneous wound healing were also impaired in diabetic or hypercortisolemic rats. The ROS suppressors EUK-134 and α-lipoic acid, or small interfering RNA (siRNA)-mediated silencing of JNK expression, restored IGF1 sensitivity both in vitro and in vivo, and also ameliorated the impairment in IGF1-mediated wound responses during diabetes, inflammation and hypercortisolemia. Our data advance the notion that ROS constitute a convergence nexus for the development of IGF1 resistance and impaired wound healing under different but pathophysiologically relevant clinical settings, with a proof of concept for the beneficial effect of ROS suppressors.
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Affiliation(s)
- Milad S Bitar
- Department of Pharmacology and Toxicology, School of Medicine, PO Box 24923, Safat 13110, Kuwait.
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44
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Yeap BB, Chubb SAP, McCaul KA, Flicker L, Ho KKY, Golledge J, Hankey GJ, Norman PE. Associations of IGF1 and its binding proteins with abdominal aortic aneurysm and aortic diameter in older men. Eur J Endocrinol 2012; 166:191-7. [PMID: 22113073 DOI: 10.1530/eje-11-0725] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Abdominal aortic aneurysm (AAA) is most prevalent in older men. GH secretion declines with age resulting in reduced IGF1 levels. IGF1 and its binding proteins (IGFBPs) are expressed in vasculature, and lower IGF1 levels have been associated with cardiovascular risk factors and disease. However, the relationship of the IGF1 system with aortic dilation and AAA is unclear. We tested the hypothesis that circulating IGF1 and IGFBPs are associated with AAA and aortic diameter in older men. DESIGN A cross-sectional analysis involving 3981 community-dwelling men aged 70-89 years was performed. METHODS Abdominal aortic diameter was measured by ultrasound. Plasma total IGF1, IGFBP1 and IGFBP3 were measured by immunoassays. RESULTS After adjustment for age, body mass index, waist:hip ratio, smoking, hypertension, dyslipidemia, diabetes, coronary heart disease and serum creatinine, a higher IGF1 level was associated with AAA (odds ratio (OR)/1 s.d. increase 1.18, 95% confidence interval (CI) 1.05-1.33, P=0.006), as was the ratio of IGF1/IGFBP3 (OR=1.22, 95% CI 1.10-1.35, P<0.001). Highest IGF1 concentrations compared with lowest quintile were significantly associated with AAA (quintile (Q) 5 vs Q1: OR=1.80, 95% CI 1.20-2.70, P=0.004) as were IGF1/IGFBP3 ratios (Q5 vs Q1: OR=2.52, 95% CI 1.59-4.02, P<0.001). IGF1 and IGFBP1 were independently associated with aortic diameter (β=0.200, 95% CI 0.043-0.357, P=0.012 and β=0.274, 95% CI 0.098-0.449, P=0.002 respectively). CONCLUSIONS In older men, higher IGF1 and an increased ratio of IGF1/IGFBP3 are associated with AAA, while IGFBP1 is independently associated with increased aortic diameter. Components of the IGF1 system may contribute to, or be a marker for, aortic dilation in ageing men.
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Affiliation(s)
- Bu B Yeap
- School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.
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45
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Savastano S, Balato N, Gaudiello F, Di Somma C, Brancato V, Colao A, Ayala F, Tarantino G. Insulin-like Growth Factor-1, Psoriasis, and Inflammation: A Ménage à Trois? EUR J INFLAMM 2011; 9:277-283. [DOI: 10.1177/1721727x1100900308] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025] Open
Abstract
Psoriatic patients have an accumulation of metabolic syndrome (MS) and cardiovascular diseases (CVD), likely mediated by systemic inflammation, and exhibiting low circulating levels of insulin-like growth factor (IGF)-I, a marker of MS and CVD in the general population. The aim of this study is to determine the association of IGF-I and inflammation, and to assess the cardio-metabolic risk calculating the visceral adiposity index (VAI), in a group of psoriatic patients without MS. IGF-I, fibrinogen, C-reactive protein (CRP), and interleukin (IL)-6 levels were determined in 20 patients with moderate to severe psoriasis (age range 23–77 yrs) without MS, according to criteria of the National Cholesterol Education Program's Adult Panel III (ATP III), and 20 age- and BMI-matched controls. The standard deviation score (SDS) of IGF-I levels according to age (zSDS), the homeostasis model assessment of insulin resistance (HOMA-IR), the whole-body insulin sensitivity index (ISI), and VAI were also calculated. Psoriasis Area and Severity Index (PASI) mean value was 17.8±11. HDL cholesterol and IGF-I zSDS values were lower (p<0.001) and waist circumference (p<0.001), VAI, fibrinogen, and IL-6 (p<0.005) were higher compared with controls, while HOMA-IR and ISI were not statistically different. Lower IGF-I zSDS values were associated to higher values of BMI (p=0.04), waist circumference, VAI (p<0.001), PASI (p=0.011), or IL-6 (p<0.001). At the multivariate analysis PASI was the major determinant of IGF-I zSDS (p=0.016), accounting for 37% of its variability. In a subset of psoriatic patients without MS, chronic inflammation might be an important modulator of low IGF-I status, as a further possible mechanistic link between psoriasis and associated metabolic co-morbidities. The negative correlation between age-related IGF-I values and VAI suggest the involvement of adipocyte dysfunction in low IGF-I status more than MS per se. Further studies are needed to address whether these results are valid also for other psoriatic patients.
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Affiliation(s)
- S. Savastano
- Department of Molecular and Clinical
Endocrinology and Oncology, Division of Endocrinology, Federico II University
Medical School of Naples
| | - N. Balato
- Department of Systematic Pathology,
Division of Clinical Dermatology, Federico II University Medical School of
Naples
| | - F. Gaudiello
- Department of Systematic Pathology,
Division of Clinical Dermatology, Federico II University Medical School of
Naples
| | | | - V. Brancato
- Department of Molecular and Clinical
Endocrinology and Oncology, Division of Endocrinology, Federico II University
Medical School of Naples
| | - A. Colao
- Department of Molecular and Clinical
Endocrinology and Oncology, Division of Endocrinology, Federico II University
Medical School of Naples
| | - F. Ayala
- Department of Systematic Pathology,
Division of Clinical Dermatology, Federico II University Medical School of
Naples
| | - G. Tarantino
- Department of Clinical and
Experimental Medicine, Federico II University Medical School of Naples, Italy
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Gupta D, Gardner M, Whaley-Connell A. Role of Growth Hormone Deficiency and Treatment in Chronic Kidney Disease. Cardiorenal Med 2011; 1:174-182. [PMID: 22258540 PMCID: PMC3150959 DOI: 10.1159/000329930] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Malnutrition and inflammation are strong predictors of mortality in advanced kidney disease, especially in patients on renal replacement therapy. The complex relationship between kidney disease, uremia, and malnutrition significantly contributes to the increased morbidity and mortality in this patient population potentially through a relative deficiency in growth hormone (GH). With an approximate 26 million Americans currently affected by some stage of chronic kidney disease and a predicted 750,000 people to be on dialysis by 2020, there is a need to develop innovative strategies aimed at reducing the high mortality seen in dialysis patients. We will review evidence on one such intervention with infusion of recombinant GH to improve the nutritional and inflammatory state, thereby expecting to improve the mortality and morbidity in this patient population.
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Affiliation(s)
- Diptesh Gupta
- Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
| | - Michael Gardner
- Division of Endocrinology and Metabolism, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
| | - Adam Whaley-Connell
- Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Division of Nephrology and Hypertension, Harry S. Truman VA Medical Center and University of Missouri-Columbia, Columbia, Mo., USA
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Allard JB, Duan C. Comparative endocrinology of aging and longevity regulation. Front Endocrinol (Lausanne) 2011; 2:75. [PMID: 22654825 PMCID: PMC3356063 DOI: 10.3389/fendo.2011.00075] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Accepted: 10/28/2011] [Indexed: 01/06/2023] Open
Abstract
Hormones regulate growth, development, metabolism, and other complex processes in multicellular animals. For many years it has been suggested that hormones may also influence the rate of the aging process. Aging is a multifactorial process that causes biological systems to break down and cease to function in adult organisms as time passes, eventually leading to death. The exact underlying causes of the aging process remain a topic for debate, and clues that may shed light on these causes are eagerly sought after. In the last two decades, gene mutations that result in delayed aging and extended longevity have been discovered, and many of the affected genes have been components of endocrine signaling pathways. In this review we summarize the current knowledge on the roles of endocrine signaling in the regulation of aging and longevity in various animals. We begin by discussing the notion that conserved systems, including endocrine signaling pathways, "regulate" the aging process. Findings from the major model organisms: worms, flies, and rodents, are then outlined. Unique lessons from studies of non-traditional models: bees, salmon, and naked mole rats, are also discussed. Finally, we summarize the endocrinology of aging in humans, including changes in hormone levels with age, and the involvement of hormones in aging-related diseases. The most well studied and widely conserved endocrine pathway that affects aging is the insulin/insulin-like growth factor system. Mutations in genes of this pathway increase the lifespan of worms, flies, and mice. Population genetic evidence also suggests this pathway's involvement in human aging. Other hormones including steroids have been linked to aging only in a subset of the models studied. Because of the value of comparative studies, it is suggested that the aging field could benefit from adoption of additional model organisms.
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Affiliation(s)
- John B. Allard
- Department of Molecular, Cellular, and Developmental Biology, University of MichiganAnn Arbor, MI, USA
| | - Cunming Duan
- Department of Molecular, Cellular, and Developmental Biology, University of MichiganAnn Arbor, MI, USA
- *Correspondence: Cunming Duan, Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Natural Science Building, Ann Arbor, MI 48109, USA. e-mail:
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