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Mladenova IL, Tan EF, Ng JY, Sharma P. Non-alcoholic fatty liver disease (NAFLD) and its association to cardiovascular disease: A comprehensive meta-analysis. JRSM Cardiovasc Dis 2025; 14:20480040251325929. [PMID: 40123646 PMCID: PMC11930486 DOI: 10.1177/20480040251325929] [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: 01/04/2024] [Revised: 11/13/2024] [Accepted: 11/18/2024] [Indexed: 03/25/2025] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) affects up to nearly a third of the Western population and has been inconsistently associated with cardiovascular diseases (CVDs). Therefore, we conducted a comprehensive meta-analysis to quantify the correlation of NAFLD with all major vascular diseases, acute coronary syndrome (ACS), subclinical atherosclerosis and endothelial dysfunction. Methods We searched PubMed and Embase for studies looking at the relationship between NAFLD and cardiovascular diseases published through September 2023. The parameters we used to assess cardiovascular diseases include acute coronary syndrome, brachial flow-mediated dilatation (FMD), serum asymmetric dimethylarginine (ADMA), carotid intima-media thickness (CIMT), and carotid stenosis (>50%). Data from these studies were then collected and meta-analysis was performed using the random effects model. RevMan v5.4 was used for statistical analysis. Results We interrogated a total of 114 publications which met our inclusion criteria. NAFLD patients showed statistically significant reduction in FMD% [MD: -4.83 (95% CI: -5.84 to 3.81, p < .00001)] and increased serum ADMA [MD: 0.08 (95% CI: 0.05-0.11, p < .00001)]. Mean CIMT was also increased in NAFLD patients [MD 0.13 (95% CI: 0.12-0.14, p < .00001)]. NAFLD showed a higher prevalence of pathological CIMT [MD: 0.11 (95% CI: 0.10-0.12, p < .00001)] and increased carotid plaques [OR: 2.08 (95% CI: 1.52-2.86, p < .00001)]. Furthermore, we demonstrated statistically significant increase in cardiovascular diseases among NAFLD patients compared to controls [OR: 1.92 (95% CI: 1.53-2.41, p < .00001)]. Conclusion NAFLD is a strong predictor for endothelial dysfunction, subclinical atherosclerosis and cardiovascular disease. Further studies are required to determine whether incidental findings of fatty liver on abdominal ultrasonography should prompt the need for detailed assessment of other CVD risk factors.
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Affiliation(s)
| | - Eu Fon Tan
- Queen Mary University of London, London, UK
| | | | - Pankaj Sharma
- Institute of Cardiovascular Research, Royal Holloway University, Egham, Greater London, UK
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Ktenopoulos N, Sagris M, Gerogianni M, Pamporis K, Apostolos A, Balampanis K, Tsioufis K, Toutouzas K, Tousoulis D. Non-Alcoholic Fatty Liver Disease and Coronary Artery Disease: A Bidirectional Association Based on Endothelial Dysfunction. Int J Mol Sci 2024; 25:10595. [PMID: 39408924 PMCID: PMC11477211 DOI: 10.3390/ijms251910595] [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: 08/24/2024] [Revised: 09/23/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is regarded as a liver manifestation of metabolic syndrome. It is linked to insulin resistance, obesity, and diabetes mellitus, all of which increase the risk of cardiovascular complications. Endothelial dysfunction (EnD) constitutes the main driver in the progression of atherosclerosis and coronary artery disease (CAD). Several pathophysiological alterations and molecular mechanisms are involved in the development of EnD in patients with NAFLD. Our aim is to examine the association of NAFLD and CAD with the parallel assessment of EnD, discussing the pathophysiological mechanisms and the genetic background that underpin this relationship. This review delves into the management of the condition, exploring potential clinical implications and available medical treatment options to facilitate the deployment of optimal treatment strategies for these patients.
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Affiliation(s)
- Nikolaos Ktenopoulos
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
| | - Marios Sagris
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
| | - Maria Gerogianni
- Endocrine Unit, 2nd Propaedeutic Department of Internal Medicine, School of Medicine, Research Institute and Diabetes Center, Attikon University Hospital, National and Kapodistrian University of Athens, 12641 Athens, Greece;
- Second Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Konstantinos Pamporis
- Department of Hygiene, Social-Preventive Medicine & Medical Statistics, Medical School, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece;
| | - Anastasios Apostolos
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
| | - Konstantinos Balampanis
- Second Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Konstantinos Tsioufis
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
| | - Konstantinos Toutouzas
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
| | - Dimitris Tousoulis
- First Department of Cardiology, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.S.); (A.A.); (K.T.); (K.T.); (D.T.)
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Masuda A, Nakamura T, Iwamoto H, Suzuki H, Sakaue T, Tanaka T, Imamura Y, Mori N, Koga H, Kawaguchi T. Ex-vivo expanded CD34 + cell transplantation alleviates fibrotic liver injury via innate immune modulation in metabolic dysfunction-associated steatohepatitis mice. Cytotherapy 2024; 26:899-909. [PMID: 38678462 DOI: 10.1016/j.jcyt.2024.03.488] [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: 12/25/2023] [Revised: 03/11/2024] [Accepted: 03/18/2024] [Indexed: 05/01/2024]
Abstract
BACKGROUND In drug-induced liver injury, vascular endothelial progenitor cells, specifically the CD34+ cell fractions, have been found to decrease liver fibrosis and promote regeneration. However, it is unclear whether CD34+ cell transplantation has anti-fibrogenic effects on MASH, which has previously been treated effectively with anti-angiogenic therapy. We investigated the efficacy of ex vivo-expanded CD34+ cells in treating MASH livers. MATERIALS AND METHODS Diet-induced MASH mice were fed a choline-deficient, L-amino acid-defined, high-fat diet for 12 or 20 weeks, and were designated as a mild and a severe fibrosis model, respectively. Mouse bone marrow CD34+ cells were expanded for 7 days, transplanted into each mouse once or twice 2 weeks later, and sacrificed at 4 weeks after the first transplantation. RESULTS Expanded CD34+ cell transplantation ameliorated liver fibrosis, regardless of fibrosis degree, as indicated by the decrease in α-smooth muscle actin-positive cells, hydroxyproline concentration, and fibrogenic gene expression of Col1a1 and Timp1. Furthermore, engrafted CD34+ cells reduced alanine transaminase levels, the number of TUNEL+ hepatocytes, and 8-OHdG concentration. RNA-sequencing data showed that "defense response to virus" was the most down-regulated category in the Gene Ontology analysis and subsequent analysis revealed the suppression of RIG-I-like receptors/Irf7/Stat1/Cxcl10 axis in expanded CD34+ cell-transplanted livers. Finally, the downregulation of CXCL10 expression inhibits the mobilization of inflammatory immune cells, macrophages, T cells, and natural killer cells to the MASH liver. CONCLUSIONS These findings suggest that transplanted expanded CD34+ cells alleviate fibrotic liver injury in MASH mouse models through possible modulation of the innate immune response, which is abnormally activated by hepatocyte lipotoxicity.
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Affiliation(s)
- Atsutaka Masuda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Toru Nakamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan.
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Takahiko Sakaue
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Toshimitsu Tanaka
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Yasuko Imamura
- Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Nobuyuki Mori
- Department of Social Welfare, Kyushu University of Nursing and Social Welfare, Tamana, Kumamoto, 8650061, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan
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Zhang B, Li J, Zeng C, Tao C, He Q, Liu C, Zheng Z, Zhao Z, Mou S, Sun W, Wang J, Zhang Q, Wang R, Zhang Y, Ge P, Zhang D. Nonalcoholic fatty liver disease is an independent risk factor for ischemic stroke after revascularization in patients with Moyamoya disease: a prospective cohort study. Lipids Health Dis 2024; 23:80. [PMID: 38494486 PMCID: PMC10944598 DOI: 10.1186/s12944-024-02065-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/27/2024] [Indexed: 03/19/2024] Open
Abstract
BACKGROUND The study aimed to investigate the association between nonalcoholic fatty liver disease (NAFLD) and ischemic stroke events after revascularization in patients with Moyamoya disease (MMD). METHODS This study prospectively enrolled 275 MMD patients from September 2020 to December 2021. Patients with alcoholism and other liver diseases were excluded. NAFLD was confirmed by CT imaging or abdominal ultrasonography. Stroke events and modified Rankin Scale (mRS) scores at the latest follow-up were compared between the two groups. RESULTS A total of 275 patients were enrolled in the study, among which 65 were diagnosed with NAFLD. Univariate logistic regression analysis showed that NAFLD (P = 0.029) was related to stroke events. Multivariate logistic regression analysis showed that NAFLD is a predictor of postoperative stroke in MMD patients (OR = 27.145, 95% CI = 2.031-362.81, P = 0.013). Kaplan-Meier analysis showed that compared with MMD patients with NAFLD, patients in the control group had a longer stroke-free time (P = 0.004). Univariate Cox analysis showed that NAFLD (P = 0.016) was associated with ischemic stroke during follow-up in patients with MMD. Multivariate Cox analysis showed that NAFLD was an independent risk factor for stroke in patients with MMD (HR = 10.815, 95% CI = 1.259-92.881, P = 0.030). Furthermore, fewer patients in the NAFLD group had good neurologic status (mRS score ≤ 2) than the control group (P = 0.005). CONCLUSION NAFLD was an independent risk factor for stroke in patients with MMD after revascularization and worse neurological function outcomes.
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Affiliation(s)
- Bojian Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Junsheng Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Chaofan Zeng
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Chuming Tao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Qiheng He
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Chenglong Liu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Zhiyao Zheng
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Zhikang Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Siqi Mou
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Wei Sun
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Jia Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Qian Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Rong Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Yan Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
| | - Peicong Ge
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
- China National Clinical Research Center for Neurological Diseases, Beijing, China.
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China.
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China.
- Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China.
| | - Dong Zhang
- Department of Neurosurgery, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China.
- Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
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Huang DQ, Downes M, Evans RM, Witztum JL, Glass CK, Loomba R. Shared Mechanisms between Cardiovascular Disease and NAFLD. Semin Liver Dis 2022; 42:455-464. [PMID: 36008083 PMCID: PMC9828940 DOI: 10.1055/a-1930-6658] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The burden of nonalcoholic fatty liver disease (NAFLD) is rising globally. Cardiovascular disease is the leading cause of death in patients with NAFLD. Nearly half of individuals with NAFLD have coronary heart disease, and more than a third have carotid artery atherosclerosis. Individuals with NAFLD are at a substantially higher risk of fatal and nonfatal cardiovascular events. NAFLD and cardiovascular disease share multiple common disease mechanisms, such as systemic inflammation, insulin resistance, genetic risk variants, and gut microbial dysbiosis. In this review, we discuss the epidemiology of cardiovascular disease in NAFLD, and highlight common risk factors. In addition, we examine recent advances evaluating the shared disease mechanisms between NAFLD and cardiovascular disease. In conclusion, multidisciplinary collaborations are required to further our understanding of the complex relationship between NAFLD and cardiovascular disease and potentially identify therapeutic targets.
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Affiliation(s)
- Daniel Q. Huang
- NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, San Diego, California
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Michael Downes
- Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, California
| | - Ronald M. Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, California
| | - Joseph L. Witztum
- Division of Endocrinology and Metabolism, Department of Medicine, University California San Diego, San Diego, California
| | - Christopher K. Glass
- Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, California
- Department of Medicine, University of California San Diego, San Diego, California
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, San Diego, California
- Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, San Diego, California
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Nasiri-Ansari N, Androutsakos T, Flessa CM, Kyrou I, Siasos G, Randeva HS, Kassi E, Papavassiliou AG. Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review. Cells 2022; 11:2511. [PMID: 36010588 PMCID: PMC9407007 DOI: 10.3390/cells11162511] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/07/2022] [Accepted: 08/10/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. It is strongly associated with obesity, type 2 diabetes (T2DM), and other metabolic syndrome features. Reflecting the underlying pathogenesis and the cardiometabolic disorders associated with NAFLD, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has recently been proposed. Indeed, over the past few years, growing evidence supports a strong correlation between NAFLD and increased cardiovascular disease (CVD) risk, independent of the presence of diabetes, hypertension, and obesity. This implies that NAFLD may also be directly involved in the pathogenesis of CVD. Notably, liver sinusoidal endothelial cell (LSEC) dysfunction appears to be implicated in the progression of NAFLD via numerous mechanisms, including the regulation of the inflammatory process, hepatic stellate activation, augmented vascular resistance, and the distortion of microcirculation, resulting in the progression of NAFLD. Vice versa, the liver secretes inflammatory molecules that are considered pro-atherogenic and may contribute to vascular endothelial dysfunction, resulting in atherosclerosis and CVD. In this review, we provide current evidence supporting the role of endothelial cell dysfunction in the pathogenesis of NAFLD and NAFLD-associated atherosclerosis. Endothelial cells could thus represent a "golden target" for the development of new treatment strategies for NAFLD and its comorbid CVD.
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Affiliation(s)
- Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
| | - Gerasimos Siasos
- Third Department of Cardiology, ‘Sotiria’ Thoracic Diseases General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Ng C, Lee KL, Muthiah MD, Wu KX, Chioh FWJ, Tan K, Soon GST, Shabbir A, Loo WM, Low ZS, Chen Q, Tan NS, Ng HH, Dan YY, Cheung C. Endothelial‐immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease. EMBO Rep 2022; 23:e54271. [PMID: 35403791 PMCID: PMC9171677 DOI: 10.15252/embr.202154271] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/19/2022] [Accepted: 03/24/2022] [Indexed: 11/17/2022] Open
Abstract
The top cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD) is cardiovascular complications. However, mechanisms of NAFLD‐associated vasculopathy remain understudied. Here, we show that blood outgrowth endothelial cells (BOECs) from NAFLD subjects exhibit global transcriptional upregulation of chemokines and human leukocyte antigens. In mouse models of diet‐induced NAFLD, we confirm heightened endothelial expressions of CXCL12 in the aortas and the liver vasculatures, and increased retention of infiltrated leukocytes within the vessel walls. To elucidate endothelial‐immune crosstalk, we performed immunoprofiling by single‐cell analysis, uncovering T cell intensification in NAFLD patients. Functionally, treatment with a CXCL12‐neutralizing antibody is effective at moderating the enhanced chemotactic effect of NAFLD BOECs in recruiting CD8+ T lymphocytes. Interference with the CXCL12‐CXCR4 axis using a CXCR4 antagonist also averts the impact of immune cell transendothelial migration and restores endothelial barrier integrity. Clinically, we detect threefold more circulating damaged endothelial cells in NAFLD patients than in healthy controls. Our work provides insight into the modulation of interactions with effector immune cells to mitigate endothelial injury in NAFLD.
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Affiliation(s)
- Chun‐Yi Ng
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | - Khang Leng Lee
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | - Mark Dhinesh Muthiah
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Department of Medicine National University Health System Singapore Singapore
| | - Kan Xing Wu
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | | | - Konstanze Tan
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | | | - Asim Shabbir
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Department of Surgery University Surgical Cluster National University Health System Singapore Singapore
| | - Wai Mun Loo
- Department of Medicine National University Health System Singapore Singapore
| | - Zun Siong Low
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology Agency for Science Technology and Research (A*STAR) Singapore Singapore
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
- School of Biological Sciences Nanyang Technological University Singapore Singapore
| | - Huck Hui Ng
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Institute of Molecular and Cell Biology Agency for Science Technology and Research (A*STAR) Singapore Singapore
- School of Biological Sciences Nanyang Technological University Singapore Singapore
- Genome Institute of Singapore Agency for Science Technology and Research (A*STAR) Singapore Singapore
| | - Yock Young Dan
- Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
- Department of Medicine National University Health System Singapore Singapore
| | - Christine Cheung
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore
- Institute of Molecular and Cell Biology Agency for Science Technology and Research (A*STAR) Singapore Singapore
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Duan Y, Pan X, Luo J, Xiao X, Li J, Bestman PL, Luo M. Association of Inflammatory Cytokines With Non-Alcoholic Fatty Liver Disease. Front Immunol 2022; 13:880298. [PMID: 35603224 PMCID: PMC9122097 DOI: 10.3389/fimmu.2022.880298] [Citation(s) in RCA: 171] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/11/2022] [Indexed: 01/30/2023] Open
Abstract
Background Inflammatory cytokines have been considered to be significant factors contributing to the development and progression of non-alcoholic fatty liver disease (NAFLD). However, the role of inflammatory cytokines in NAFLD remains inconclusive. Objective This study aimed to evaluate the association between inflammatory cytokines and NAFLD. Methods PubMed, Web of Science, the Cochrane Library, and EMBASE databases were searched until 31 December 2021 to identify eligible studies that reported the association of inflammatory cytokine with NAFLD and its subtypes. We pooled odds ratios (ORs) and hazard risk (HRs) with 95% confidence intervals (CIs) and conducted heterogeneity tests. Sensitivity analysis and analysis for publication bias were also carried out. Results The search in the databases identified 51 relevant studies that investigated the association between 19 different inflammatory cytokines and NAFLD based on 36,074 patients and 47,052 controls. The results of the meta-analysis showed significant associations for C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) with NAFLD (ORs of 1.41, 1.08, 1.50, 1.15 and 2.17, respectively). In contrast, we observed non-significant associations for interferon-γ (IFN-γ), insulin-like growth factor (IGF-II), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), monocyte chemoattractant protein-1(MCP-1), and transforming growth factor-β (TGF-β) with NAFLD. Our results also showed that CRP, IL-1β, and TNF-α were significantly associated with non-alcoholic steatohepatitis (NASH) and hepatic fibrosis. Conclusions Our results indicated that increased CRP, IL‐1β, IL-6, TNF‐α, and ICAM-1 concentrations were significantly associated with increased risks of NAFLD. These inflammatory mediators may serve as biomarkers for NAFLD subjects and expect to provide new insights into the aetiology of NAFLD as well as early diagnosis and intervention.
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Affiliation(s)
- Yamei Duan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiongfeng Pan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Jiayou Luo
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiang Xiao
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Jingya Li
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Prince L. Bestman
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Miyang Luo
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
- *Correspondence: Miyang Luo,
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9
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Ogresta D, Mrzljak A, Cigrovski Berkovic M, Bilic-Curcic I, Stojsavljevic-Shapeski S, Virovic-Jukic L. Coagulation and Endothelial Dysfunction Associated with NAFLD: Current Status and Therapeutic Implications. J Clin Transl Hepatol 2022; 10:339-355. [PMID: 35528987 PMCID: PMC9039716 DOI: 10.14218/jcth.2021.00268] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/24/2021] [Accepted: 10/08/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely related to insulin resistance, type 2 diabetes mellitus and obesity. It is considered a multisystem disease and there is a strong association with cardiovascular disease and arterial hypertension, which interfere with changes in the coagulation system. Coagulation disorders are common in patients with hepatic impairment and are dependent on the degree of liver damage. Through a review of the literature, we consider and discuss possible disorders in the coagulation cascade and fibrinolysis, endothelial dysfunction and platelet abnormalities in patients with NAFLD.
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Affiliation(s)
- Doris Ogresta
- Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb, Croatia
- Department of Medicine, University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Maja Cigrovski Berkovic
- Department for Endocrinology, Diabetes and Pharmacology, University Hospital Dubrava, Zagreb, Croatia
- Department of Kinesiological Anthropology and Methodology, Faculty of Kinesiology, University of Zagreb
- Department of Pharmacology, Faculty of Medicine, University of JJ Strossmayer, Osijek, Croatia
| | - Ines Bilic-Curcic
- Department of Pharmacology, Faculty of Medicine, University of JJ Strossmayer, Osijek, Croatia
- Department of Diabetes, Endocrinology and Metabolism Disorders, University Hospital Osijek, Osijek, Croatia
| | | | - Lucija Virovic-Jukic
- Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
- Department of Medicine, University of Zagreb, School of Medicine, Zagreb, Croatia
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10
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Endothelial Progenitor Cells Dysfunctions and Cardiometabolic Disorders: From Mechanisms to Therapeutic Approaches. Int J Mol Sci 2021; 22:ijms22136667. [PMID: 34206404 PMCID: PMC8267891 DOI: 10.3390/ijms22136667] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/10/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic syndrome (MetS) is a cluster of several disorders, such as hypertension, central obesity, dyslipidemia, hyperglycemia, insulin resistance and non-alcoholic fatty liver disease. Despite health policies based on the promotion of physical exercise, the reduction of calorie intake and the consumption of healthy food, there is still a global rise in the incidence and prevalence of MetS in the world. This phenomenon can partly be explained by the fact that adverse events in the perinatal period can increase the susceptibility to develop cardiometabolic diseases in adulthood. Individuals born after intrauterine growth restriction (IUGR) are particularly at risk of developing cardiovascular diseases (CVD) and metabolic disorders later in life. It has been shown that alterations in the structural and functional integrity of the endothelium can lead to the development of cardiometabolic diseases. The endothelial progenitor cells (EPCs) are circulating components of the endothelium playing a major role in vascular homeostasis. An association has been found between the maintenance of endothelial structure and function by EPCs and their ability to differentiate and repair damaged endothelial tissue. In this narrative review, we explore the alterations of EPCs observed in individuals with cardiometabolic disorders, describe some mechanisms related to such dysfunction and propose some therapeutical approaches to reverse the EPCs dysfunction.
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11
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Kumboyono K, Chomsy IN, Nurwidyaningtyas W, Cesa FY, Tjahjono CT, Wihastuti TA. Differences in senescence of late Endothelial Progenitor Cells in non-smokers and smokers. Tob Induc Dis 2021; 19:10. [PMID: 34131419 PMCID: PMC8171388 DOI: 10.18332/tid/135320] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/30/2021] [Accepted: 03/31/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Endothelial Progenitor Cells (EPCs) are part of hematopoietic stem cells that differentiate into endothelial cells during their blood vessels' maturation process. The role of EPCs is widely known to contribute to repair of the vascular wall when endothelial dysfunction occurs. However, various risk factors for cardiovascular disease (CVD) influence EPC performance, leading to endothelial dysfunction. One EPC dysfunction is decreased amount of EPC mobilization to the injured tissue. EPC dysfunction reduces the angiogenetic function of EPCs. The vital maturation process that the EPCs must pass is the late phase. The dysfunction of late EPCs is known as senescence. This study aimed to identify and compare senescence of late EPCs, through CD62E and CD41 markers, in non-smokers and smokers as a risk factor for CVD. METHODS EPC collection was from peripheral mononuclear cells (PBMCs) in non-smokers (n=30) and smokers (n=31). The EPCs were then marked by CD62E/CD41 and senescence β-galactosidase assay using FACS. Identification of senescence cells was based on fluorescence with DAPI. RESULTS Positive percentage of late EPCs in non-smokers was not significantly different from that in smokers (p=0.014). The number of senescent late EPCs in smokers was higher than in non-smokers (p<0.0001). CONCLUSIONS Endothelial progenitor cells that experienced senescence in the smokers showed EPC dysfunction, which resulted in decreased cell angiogenic function. Further research is needed to explain the mechanism of re-endothelialization failure in EPC dysfunction due to smoking.
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Affiliation(s)
- Kumboyono Kumboyono
- School of Nursing, Faculty of Medicine, University of Brawijaya, Malang, Indonesia
| | | | | | | | - Cholid Tri Tjahjono
- Department of Cardiology, Faculty of Medicine, University of Brawijaya, Malang, Indonesia
| | - Titin Andri Wihastuti
- Department of Basic Nursing Science, Faculty of Medicine, University of Brawijaya, Malang, Indonesia
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12
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Muzurović E, Mikhailidis DP, Mantzoros C. Non-alcoholic fatty liver disease, insulin resistance, metabolic syndrome and their association with vascular risk. Metabolism 2021; 119:154770. [PMID: 33864798 DOI: 10.1016/j.metabol.2021.154770] [Citation(s) in RCA: 164] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 02/07/2023]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases, is rising. About 25% of adults worldwide are probably affected by NAFLD. Insulin resistance (IR) and fat accumulation in the liver are strongly related. The association between NAFLD, metabolic syndrome (MetS) and IR is established, but an independent impact of NAFLD on vascular risk and progression of cardiovascular (CV) disease (CVD) still needs to be confirmed. This narrative review considers the evidence regarding the link between NAFLD, IR and CVD risk. There is strong evidence for a "concomitantly rising incidence" of NAFLD, IR, MetS and CVD but there is no definitive evidence regarding whether NAFLD is, or is not, an independent and significant risk factor the development of CVD. There are also considerations that type 2 diabetes mellitus (T2DM) may be a common link between NAFLD/non-alcoholic steatohepatitis (NASH) and CVD. NAFLD may be associated with widespread abnormal peri-organ or intra-organ fat (APIFat) deposition (e.g. epicardial adipose tissue) which may further contribute to CV risk. It is clear that NAFLD patients have a greater CV risk (independent or not) which needs to be addressed in clinical practice.
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Affiliation(s)
- Emir Muzurović
- Department of Internal Medicine, Endocrinology Section, Clinical Centre of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro; Faculty of Medicine, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro.
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), Pond Street, London NW3 2QG, UK; Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Christos Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA 02115, USA
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13
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Ramadan MS, Russo V, Nigro G, Durante-Mangoni E, Zampino R. Interplay between Heart Disease and Metabolic Steatosis: A Contemporary Perspective. J Clin Med 2021; 10:1569. [PMID: 33917867 PMCID: PMC8068259 DOI: 10.3390/jcm10081569] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 03/26/2021] [Accepted: 04/03/2021] [Indexed: 12/12/2022] Open
Abstract
The liver-heart axis is a growing field of interest owing to rising evidence of complex bidirectional interplay between the two organs. Recent data suggest non-alcoholic fatty liver disease (NAFLD) has a significant, independent association with a wide spectrum of structural and functional cardiac diseases, and seems to worsen cardiovascular disease (CVD) prognosis. Conversely, the effect of cardiac disease on NAFLD is not well studied and data are mostly limited to cardiogenic liver disease. We believe it is important to further investigate the heart-liver relationship because of the tremendous global health and economic burden the two diseases pose, and the impact of such investigations on clinical decision making and management guidelines for both diseases. In this review, we summarize the current knowledge on NAFLD diagnosis, its systemic manifestations, and associations with CVD. More specifically, we review the pathophysiological mechanisms that govern the interplay between NAFLD and CVD and evaluate the relationship between different CVD treatments and NAFLD progression.
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Affiliation(s)
- Mohammad Said Ramadan
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Vincenzo Russo
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Gerardo Nigro
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Emanuele Durante-Mangoni
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
| | - Rosa Zampino
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
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14
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Sasson A, Kristoferson E, Batista R, McClung JA, Abraham NG, Peterson SJ. The pivotal role of heme Oxygenase-1 in reversing the pathophysiology and systemic complications of NAFLD. Arch Biochem Biophys 2020; 697:108679. [PMID: 33248947 DOI: 10.1016/j.abb.2020.108679] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/03/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023]
Abstract
The pathogenesis and molecular pathways involved in non-alcoholic fatty liver disease (NAFLD) are reviewed, as well as what is known about mitochondrial dysfunction that leads to heart disease and the progression to steatohepatitis and hepatic fibrosis. We focused our discussion on the role of the antioxidant gene heme oxygenase-1 (HO-1) and its nuclear coactivator, peroxisome proliferator-activated receptor-gamma coactivator (PGC1-α) in the regulation of mitochondrial biogenesis and function and potential therapeutic benefit for cardiac disease, NAFLD as well as the pharmacological effect they have on the chronic inflammatory state of obesity. The result is increased mitochondrial function and the conversion of white adipocyte tissue to beige adipose tissue ("browning of white adipose tissue") that leads to an improvement in signaling pathways and overall liver function. Improved mitochondrial biogenesis and function is essential to preventing the progression of hepatic steatosis to NASH and cirrhosis as well as preventing cardiovascular complications.
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Affiliation(s)
- Ariel Sasson
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Eva Kristoferson
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA
| | - Rogerio Batista
- The Mount Sinai Bone Program, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - John A McClung
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA
| | - Nader G Abraham
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA; Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, 25701, USA
| | - Stephen J Peterson
- Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA; New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY, 11215, USA.
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15
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Valencia-Rodríguez A, Vera-Barajas A, Barranco-Fragoso B, Kúsulas-Delint D, Qi X, Méndez-Sánchez N. New insights into the association between non-alcoholic fatty liver disease and atherosclerosis. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:S300. [PMID: 32016019 PMCID: PMC6976510 DOI: 10.21037/atm.2019.11.13] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 10/30/2019] [Indexed: 02/05/2023]
Affiliation(s)
| | | | | | | | - Xingshun Qi
- General Hospital of Northern Theater Command, Department of Gastroenterology. Shenyang, Liaoning 10016China
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
- Faculty of Medicine. National Autonomous University of Mexico, Mexico City, Mexico
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16
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Sehgal R, Kaur S, Shasthry SM, Agrawal T, Dwivedi V, Seth D, Ramakrishna G, Sarin SK, Trehanpati N. Natural Killer Cells Contribute to Pathogenesis of Severe Alcoholic Hepatitis by Inducing Lysis of Endothelial Progenitor Cells. Alcohol Clin Exp Res 2019; 44:78-86. [PMID: 31746472 DOI: 10.1111/acer.14242] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 11/13/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Endothelial progenitor cells (EPCs) help in neovascularization and endothelial repair during injury. Patients with cirrhosis show increased number and function of EPCs in circulation. METHODS Since natural killer (NK) cells regulate EPCs, we investigated the relationship between the 2 in alcoholic cirrhosis (AC, n = 50) and severe alcoholic hepatitis (SAH, n = 18) patients and compared with nonalcoholic cirrhosis (n = 15) and healthy controls (HC, n = 30). Levels of systemic inflammatory cytokines were measured, and coculture assays were performed between EPCs and NK cells in contact-dependent and contact-independent manner. NK cell-mediated killing of EPCs was evaluated, and expression of receptors including fractalkine (FKN) on EPCs and its cognate receptor CX3CR1 on NK cells was studied by RT-PCR assays. RESULTS Patients with SAH had higher regulated on activation, normal T cell expressed and secreted (RANTES) (p = 0.01), vascular endothelial growth factor (VEGF) (p = 0.04), IL-1β (p = 0.04), and IL-6 (p = 0.00) growth factors and proinflammatory cytokines as compared to AC and HC. Distinct populations of CD31+ CD34+ EPCs with low and high expression of CD45 were significantly lower in SAH than HC (CD45low , p = 0.03; CD45hi , p = 0.04) and AC (CD45low , p = 0.05; CD45hi , p = 0.02). SAH patients, however, showed increased functional capacity of EPCs including colony formation and LDL uptake. NK cells were reduced in SAH compared with AC (p = 0.002), however with higher granzyme ability (p < 0.001 and p = 0.04, respectively). In SAH, EPC-NK cell interaction assays showed that NK cells lysed the EPCs in both contact-dependent and contact-independent assays. Expression of interaction receptor CX3CR1 was significantly higher on NK cells (p = 0.0005), while its cognate receptor, FKN, was increased on EPCs in SAH patients as compared to HC (p = 0.0055). CONCLUSION We conclude that in SAH, NK cells induce killing of EPCs via CX3CR1/FKN axis that may be one of the key events contributing to disease severity and proinflammatory responses in SAH.
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Affiliation(s)
- Rashi Sehgal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Savneet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Tanvi Agrawal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Varsha Dwivedi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Devanshi Seth
- Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.,Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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17
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Zhao H, Zhao Y, Li X, Xu L, Jiang F, Hou W, Dong L, Cao J. Effects of Antioxidant Tempol on Systematic Inflammation and Endothelial Apoptosis in Emphysematous Rats Exposed to Intermittent Hypoxia. Yonsei Med J 2018; 59:1079-1087. [PMID: 30328323 PMCID: PMC6192890 DOI: 10.3349/ymj.2018.59.9.1079] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 08/22/2018] [Accepted: 08/23/2018] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Obstructive sleep apnea and chronic obstructive pulmonary disease are independent risk factors of cardiovascular disease (CVD), and their coexistence is known as overlap syndrome (OS). Endothelial dysfunction is the initial stage of CVD; however, underlying mechanisms linking OS and CVD are not well understood. The aim of this study was to explore whether OS can lead to more severe inflammation and endothelial apoptosis by promoting endothelial dysfunction, and to assess the intervention effects of antioxidant tempol. MATERIALS AND METHODS Male Wistar rats (n=66) were exposed to normal oxygen [normal control (NC) group], intermittent hypoxia (IH group), cigarette smoke (CH group), as well as cigarette smoke and IH (OS group). Tempol intervention was assessed in OS group treated with tempol (OST group) or NaCl (OSN group). After an 8-week challenge, lung tissues, serum, and fresh blood were harvested for analysis of endothelial markers and apoptosis. RESULTS The levels of intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, and apoptosis in circulating epithelial cells were the highest in OS group and the lowest in NC group. These levels were all greater in IH group than in CH group, and were lower in OST group than in OS and OSN groups (all p<0.001). CONCLUSION Synergistic effects of IH with cigarette smoke-induced emphysema produce a greater inflammatory status and endothelial apoptosis. OS-related inflammation and endothelial cell apoptosis may play important roles in promoting cardiovascular dysfunction, and antioxidant tempol could achieve a partial protective effect.
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Affiliation(s)
- Haiyan Zhao
- Respiratory Department of Tianjin Medical University General Hospital, Tianjin, China
| | - Yaping Zhao
- Respiratory Department of Tianjin Medical University General Hospital Airport Hospital, Tianjin, China
| | - Xin Li
- Respiratory Department of Tianjin Medical University General Hospital, Tianjin, China
| | - Leiqian Xu
- Respiratory Department of Tianjin Medical University General Hospital, Tianjin, China
| | - Fangxin Jiang
- Department of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Wanju Hou
- Respiratory Department of Tianjin Medical University General Hospital, Tianjin, China
| | - Lixia Dong
- Respiratory Department of Tianjin Medical University General Hospital, Tianjin, China.
| | - Jie Cao
- Respiratory Department of Tianjin Medical University General Hospital, Tianjin, China.
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18
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Chang T, Hsu C, Chiu C, Chou R, Huang H, Huang C, Leu H, Huang P, Chen J, Lin S. Association between echocardiographic epicardial fat thickness and circulating endothelial progenitor cell level in patients with stable angina pectoris. Clin Cardiol 2017; 40:697-703. [PMID: 28464274 PMCID: PMC6490635 DOI: 10.1002/clc.22717] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 03/21/2017] [Accepted: 03/24/2017] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Epicardial adipose tissue is associated with coronary artery disease (CAD). Circulating endothelial progenitor cell (EPC) level represents a marker of endothelial dysfunction and vascular health. However, the relationship between epicardial fat and circulating EPC remains unknown. This study aimed to investigate association between echocardiographic epicardial fat thickness (EFT) and circulating EPC level. HYPOTHESIS Epicardial fat causes inflammation and contributes to progression of CAD. METHODS We enrolled 213 consecutive patients with stable angina, and EFT was determined by echocardiography. Quantification of EPC markers (defined as CD34 + , CD34 + KDR + , CD34 + KDR + CD133 + cells) in peripheral blood samples was used to measure circulating EPCs. All patients were divided into 3 tertiles according to EFT levels: group 1, low tertile of EFT; group 2, middle tertile of EFT; and group 3, high tertile of EFT. RESULTS Among the 3 groups, CAD disease severity determined by SXscore was negatively correlated with EFT, but the difference did not reach statistical significance (P = 0.066). Additionally, patients in the high and middle tertiles of EFT had higher circulating EPC levels than did those in the low tertile of EFT (P = 0.001 and P < 0.001, respectively). In multivariate analysis, EPC level was significantly associated with echocardiographic EFT (standardized β = -0.233, P = 0.001), independent of multiple covariates. CONCLUSIONS Epicardial adipose tissue is associated with circulating EPC levels. There was a trend between epicardial fat and severity of CAD, though analysis did not reach statistical significance, and this may be attributed to the interaction between several risk factors of CAD.
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Affiliation(s)
- Ting‐Yung Chang
- Division of Cardiology, Department of Internal MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Cardiovascular Research CenterNational Yang‐Ming UniversityTaipeiTaiwan
- Division of Cardiology and Cardiovascular Research Center, Department of Internal MedicineTaipei Medical University HospitalTaipeiTaiwan
| | - Chien‐Yi Hsu
- Cardiovascular Research CenterNational Yang‐Ming UniversityTaipeiTaiwan
- Institute of Clinical MedicineNational Yang‐Ming UniversityTaipeiTaiwan
- Division of Cardiology and Cardiovascular Research Center, Department of Internal MedicineTaipei Medical University HospitalTaipeiTaiwan
- Department of Internal Medicine, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
| | - Chun‐Chih Chiu
- Division of Cardiology, Department of Internal MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Cardiovascular Research CenterNational Yang‐Ming UniversityTaipeiTaiwan
| | - Ruey‐Hsing Chou
- Division of Cardiology, Department of Internal MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Cardiovascular Research CenterNational Yang‐Ming UniversityTaipeiTaiwan
| | - Hsin‐Lei Huang
- Cardiovascular Research CenterNational Yang‐Ming UniversityTaipeiTaiwan
- Institute of Clinical MedicineNational Yang‐Ming UniversityTaipeiTaiwan
| | - Chin‐Chou Huang
- Division of Cardiology, Department of Internal MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Cardiovascular Research CenterNational Yang‐Ming UniversityTaipeiTaiwan
- Institute of PharmacologyNational Yang‐Ming UniversityTaipeiTaiwan
| | - Hsin‐Ban Leu
- Division of Cardiology, Department of Internal MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Cardiovascular Research CenterNational Yang‐Ming UniversityTaipeiTaiwan
- Institute of Clinical MedicineNational Yang‐Ming UniversityTaipeiTaiwan
| | - Po‐Hsun Huang
- Division of Cardiology, Department of Internal MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Cardiovascular Research CenterNational Yang‐Ming UniversityTaipeiTaiwan
- Institute of Clinical MedicineNational Yang‐Ming UniversityTaipeiTaiwan
| | - Jaw‐Wen Chen
- Division of Cardiology, Department of Internal MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Cardiovascular Research CenterNational Yang‐Ming UniversityTaipeiTaiwan
- Institute of PharmacologyNational Yang‐Ming UniversityTaipeiTaiwan
- Department of Medical ResearchTaipei Veterans General HospitalTaipeiTaiwan
| | - Shing‐Jong Lin
- Division of Cardiology, Department of Internal MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Cardiovascular Research CenterNational Yang‐Ming UniversityTaipeiTaiwan
- Institute of Clinical MedicineNational Yang‐Ming UniversityTaipeiTaiwan
- Department of Medical ResearchTaipei Veterans General HospitalTaipeiTaiwan
- Taipei Medical UniversityTaipeiTaiwan
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Liu X, Liu Y, Huang X, Lin G, Xie C. Endothelial progenitor cell dysfunction in acute exacerbation of chronic obstructive pulmonary disease. Mol Med Rep 2017; 16:5294-5302. [PMID: 28849108 PMCID: PMC5647060 DOI: 10.3892/mmr.2017.7260] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 02/09/2017] [Indexed: 12/14/2022] Open
Abstract
Endothelial progenitor cells (EPCs) are decreased in cardiac dysfunction morbidity associated with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Therefore, the present study aimed to assess the role of EPCs in AECOPD. Patients with AECOPD (n=27) or stable COPD (n=26) were enrolled. Systemic inflammatory markers (high-sensitivity C-reactive protein) were measured. In addition, EPCs were counted, isolated and cultured, and their proliferative, migratory, adhesive and tube-forming capabilities were determined, in cells from patients with AECOPD and stable COPD. EPC number was lower in patients with AECOPD (5.1±2.6×103/ml) compared with patients with stable COPD (6.0±3.2×103/ml). Migration assay indicated that the early-EPCs isolated from patients with AECOPD were significantly less mobile than EPCs derived from stable COPD subjects, at a stromal-cell derived factor-1α concentration of 100 ng/ml (3,550/30,000 vs. 7,853/30,000, P<0.05). C-X-C chemokine receptor-4 positivity was significantly reduced in AECOPD patients (16.1±9.9 vs. 56.33±6.3%, P<0.05). Furthermore, fewer early-EPC clusters were formed by EPCs derived from AECOPD, compared with those derived from stable COPD (8.2±0.86 vs. 14.4±1.36, P=0.027). Stable COPD late-EPCs were markedly deficient in intact tubule formation, however AECOPD late-EPCs formed no tubules. The number of AECOPD- and stable COPD-derived late-EPCs adhering to Matrigel-induced tubules was 36.8±1.85 and 20.6±1.36 (P<0.05) respectively, and the cluster of differentiation 31 positivity in late-EPCs was 79.69±1.3 and 29.1±2.47%, in AECOPD and stable COPD patients, respectively (P<0.001). The findings demonstrated that early-EPCs are decreased and dysfunctional in AECOPD patients, which may contribute to the altered vascular endothelium in this patient population.
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Affiliation(s)
- Xiaoran Liu
- Emergency Department, The Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570100, P.R. China
| | - Yangli Liu
- Respiratory Department, The First Affiliated Hospital of Sun Yat‑sen University, Institute of Respiratory Disease of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xinyan Huang
- Respiratory Department, The First Affiliated Hospital of Sun Yat‑sen University, Institute of Respiratory Disease of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Gengpeng Lin
- Respiratory Department, The First Affiliated Hospital of Sun Yat‑sen University, Institute of Respiratory Disease of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Canmao Xie
- Respiratory Department, The First Affiliated Hospital of Sun Yat‑sen University, Institute of Respiratory Disease of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
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20
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Fadini GP, Tura A, Pacini G, Avogaro A, Vigili de Kreutzenberg S. Reduced circulating stem cells associate with excess fasting and post-load NEFA exposure in healthy adults with normal glucose tolerance. Atherosclerosis 2017; 261:117-123. [DOI: 10.1016/j.atherosclerosis.2017.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 02/20/2017] [Accepted: 03/01/2017] [Indexed: 12/27/2022]
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21
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Simon TG, Corey KE, Chung RT, Giugliano R. Cardiovascular Risk Reduction in Patients with Nonalcoholic Fatty Liver Disease: The Potential Role of Ezetimibe. Dig Dis Sci 2016; 61:3425-3435. [PMID: 27714510 DOI: 10.1007/s10620-016-4330-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 09/26/2016] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is widely considered to be the hepatic manifestation of the metabolic syndrome and is closely linked to dyslipidemia, obesity, and insulin resistance. Patients with NAFLD have increased mortality when compared to the general population, primarily related to cardiovascular disease or malignancy. The biologic mechanisms that link NAFLD to cardiovascular disease include expansion of visceral adipose tissue, atherogenic dyslipidemia, impaired insulin signaling, systemic inflammation, and endothelial dysfunction. Currently, there are no approved therapies for NAFLD. It has recently been hypothesized that reducing the delivery of dietary cholesterol using the hypolipidemic agent, ezetimibe, could benefit patients with NAFLD. By potently inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) sterol receptor on intestinal enterocytes and within the liver, ezetimibe blocks exogenous cholesterol absorption and has been shown to improve biochemical markers of NAFLD, improve insulin sensitivity and decrease hepatic steatosis. This review summarizes the clinical and epidemiological evidence for the relationship between NAFLD and cardiovascular risk and examines the potential therapeutic role of ezetimibe.
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Affiliation(s)
- Tracey G Simon
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Kathleen E Corey
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Raymond T Chung
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Robert Giugliano
- Harvard Medical School, Boston, MA, USA. .,Cardiovascular Division, Brigham and Women's Hospital, 350 Longwood Avenue, 1st Floor, Boston, MA, 02215, USA.
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22
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Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications. J Hepatol 2016; 65:425-43. [PMID: 27091791 DOI: 10.1016/j.jhep.2016.04.005] [Citation(s) in RCA: 364] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 03/25/2016] [Accepted: 04/01/2016] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become one of the most frequent chronic liver diseases in the Western society and its prevalence is likely to rise even further. An increasing body of evidence shows that NAFLD is not only a potentially progressive liver disease, but also has systemic consequences. More specifically, evidence points out that NAFLD has to be considered as a significant independent risk factor for subclinical and clinical cardiovascular disease (CVD). Long-term follow-up studies demonstrate cardiovascular mortality to be the most important cause of death in NAFLD patients. Moreover, ample evidence associates NAFLD with endothelial dysfunction, increased pulse wave velocity, increased coronary arterial calcifications and increased carotid intima media thickness, all established markers for CVD. Despite of all this evidence, the mechanisms by which NAFLD causally contributes to CVD are not fully elucidated. Furthermore, an extensive overview of all potential pathophysiological mechanisms and the corresponding current data are lacking. In this review we summarise current knowledge, originating from fundamental and clinical research, that mechanistically links NAFLD to CVD. Subsequently, the impact of CVD on current clinical practice and future research in the area of NALFD are discussed.
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23
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Perera N, Indrakumar J, Abeysinghe WV, Fernando V, Samaraweera WMCK, Lawrence JS. Non alcoholic fatty liver disease increases the mortality from acute coronary syndrome: an observational study from Sri Lanka. BMC Cardiovasc Disord 2016; 16:37. [PMID: 26869052 PMCID: PMC4751701 DOI: 10.1186/s12872-016-0212-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Accepted: 02/05/2016] [Indexed: 12/22/2022] Open
Abstract
Background Non alcoholic fatty liver disease is an independent risk factor for coronary artery disease. But its effect on acute coronary syndrome is not clear. We performed this study to identify the prevalence of NAFLD in patients with ACS admitted to a tertiary care center in Sri Lanka. We also described the association of NAFLD with the severity of ACS predicted by the GRACE score. Methods We performed a descriptive study including all consecutive patients with non-fatal ACS admitted to Colombo South Teaching Hospital from 01/02/2014 to 30/04/2014. Patients with excessive alcohol consumption, established cirrhosis and patients with identified risk factors for liver disease were excluded from the study. All patients underwent ultrasound scan of liver. Results There were 120 participants, 75 (62.5 %) males and 45 (37.5 %) females with acute coronary syndrome. Average age was 61.28 ± 11.83 years. NAFLD was seen in 56 (46.7 %) patients with ACS. Patients with NAFLD had a higher GRACE score than patients without NAFLD (120.2 ± 26.9 Vs 92.3 ± 24.2, p < 0.001). Increased age and presence of NAFLD conferred a higher mortality risk from ACS as predicted by GRACE score. Patients with NAFLD had a higher predicted mortality during in-ward stay (adjusted OR 31.3, CI 2.2–439.8, p = 0.011) and at 6 months after discharge (adjusted OR 15.59, CI 1.6–130.6, p = 0.011). Conclusions Patients with NAFLD have a higher predicted mortality from acute coronary syndrome and thus require aggressive treatment of CAD. It is important to consider this novel risk factor when risk stratifying patients with ACS.
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Affiliation(s)
- Nilanka Perera
- Department of Medicine, University of Sri Jayewardenepura, Nugegoda, Sri Lanka.
| | | | | | - Vihangi Fernando
- Department of Medicine, University of Sri Jayewardenepura, Nugegoda, Sri Lanka.
| | - W M C K Samaraweera
- Department of Radiology, Colombo South Teaching Hospital, Kalubowila, Sri Lanka.
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24
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Liu HZ, Wang QY, Zhang Y, Qi DT, Li MW, Guo WQ, Ma YH, Wang LY, Chen Y, Gao CY. Pioglitazone up-regulates long non-coding RNA MEG3 to protect endothelial progenitor cells via increasing HDAC7 expression in metabolic syndrome. Biomed Pharmacother 2016; 78:101-109. [PMID: 26898430 DOI: 10.1016/j.biopha.2016.01.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 01/05/2016] [Indexed: 12/16/2022] Open
Abstract
Long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) is expressed in endothelial cells and involved in angiogenesis and vascular function. It was proposed that MEG3 participates in the process of endothelial progenitor cells (EPCs) functions in metabolic syndrome (MetS). In this study, the circulating EPCs number and function were decreased in MetS subjects. The MEG3 expression was expressed at a lower level and microRNA-140-5p (miR-140-5p) was expressed at a higher level in circulating EPCs of subjects with MetS. Pioglitazone reversed the alterations of EPCs function and the expression levels of MEG3 and miR-140-5p in EPCs. In bone marrow-derived EPCs exposed to palmitate, down-regulation of miR-140-5p canceled the increase of MEG3 expression level induced by Pioglitazone. Overexpression of MEG3 resulted in the down-regulation of miR-140-5p. The luciferase reporter assay and RIP assay showed that MEG3 targeted miR-140-5p. In addition, the HDAC7 expression levels were regulated by miR-140-5p and MEG3. These findings demonstrated that Pioglitazone up-regulated MEG3 expression to protect EPCs via decreasing miR-140-5p expression and increasing HDAC7 expression in MetS, which may be a novel therapeutic target for preventing and treating MetS.
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Affiliation(s)
- H Z Liu
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou 450003, China.
| | - Q Y Wang
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou 450003, China
| | - Y Zhang
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou 450003, China
| | - D T Qi
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou 450003, China
| | - M W Li
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou 450003, China
| | - W Q Guo
- Department of Echocardiography, Henan Provincial People's Hospital, Zhengzhou 450003, China
| | - Y H Ma
- Department of Endocrinology and Metabolism, Henan Provincial People's Hospital, Zhengzhou 450003, China
| | - L Y Wang
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou 450003, China
| | - Y Chen
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou 450003, China
| | - C Y Gao
- Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou 450003, China
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25
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Li S, Plouffe BD, Belov AM, Ray S, Wang X, Murthy SK, Karger BL, Ivanov AR. An Integrated Platform for Isolation, Processing, and Mass Spectrometry-based Proteomic Profiling of Rare Cells in Whole Blood. Mol Cell Proteomics 2015; 14:1672-83. [PMID: 25755294 DOI: 10.1074/mcp.m114.045724] [Citation(s) in RCA: 119] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Indexed: 12/29/2022] Open
Abstract
Isolation and molecular characterization of rare cells (e.g. circulating tumor and stem cells) within biological fluids and tissues has significant potential in clinical diagnostics and personalized medicine. The present work describes an integrated platform of sample procurement, preparation, and analysis for deep proteomic profiling of rare cells in blood. Microfluidic magnetophoretic isolation of target cells spiked into 1 ml of blood at the level of 1000-2000 cells/ml, followed by focused acoustics-assisted sample preparation has been coupled with one-dimensional PLOT-LC-MS methodology. The resulting zeptomole detection sensitivity enabled identification of ∼4000 proteins with injection of the equivalent of only 100-200 cells per analysis. The characterization of rare cells in limited volumes of physiological fluids is shown by the isolation and quantitative proteomic profiling of first MCF-7 cells spiked into whole blood as a model system and then two CD133+ endothelial progenitor and hematopoietic cells in whole blood from volunteers.
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Affiliation(s)
- Siyang Li
- From the ‡Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, Massachusetts; §Department of Chemical Engineering, Northeastern University, Boston, Massachusetts
| | - Brian D Plouffe
- From the ‡Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, Massachusetts; ¶Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts
| | - Arseniy M Belov
- From the ‡Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, Massachusetts; §Department of Chemical Engineering, Northeastern University, Boston, Massachusetts
| | - Somak Ray
- From the ‡Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, Massachusetts
| | - Xianzhe Wang
- From the ‡Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, Massachusetts; §Department of Chemical Engineering, Northeastern University, Boston, Massachusetts
| | - Shashi K Murthy
- From the ‡Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, Massachusetts; ¶Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts
| | - Barry L Karger
- From the ‡Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, Massachusetts; §Department of Chemical Engineering, Northeastern University, Boston, Massachusetts
| | - Alexander R Ivanov
- From the ‡Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, Massachusetts; §Department of Chemical Engineering, Northeastern University, Boston, Massachusetts
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26
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Chen DL, Huang PH, Chiang CH, Leu HB, Chen JW, Lin SJ. Phytosterols increase circulating endothelial progenitor cells and insulin-like growth factor-1 levels in patients with nonalcoholic fatty liver disease: A randomized crossover study. J Funct Foods 2015. [DOI: 10.1016/j.jff.2014.12.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
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27
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Takeuchi M, Takino JI, Sakasai-Sakai A, Takata T, Ueda T, Tsutsumi M, Hyogo H, Yamagishi SI. Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies. World J Hepatol 2014; 6:880-893. [PMID: 25544875 PMCID: PMC4269907 DOI: 10.4254/wjh.v6.i12.880] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 09/12/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease around the world. It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and can lead to fibrosis, cirrhosis, liver failure, and/or hepatocellular carcinoma. NAFLD is also associated with other medical conditions such as obesity, diabetes mellitus (DM), metabolic syndrome, hypertension, insulin resistance, hyperlipidemia, and cardiovascular disease (CVD). In diabetes, chronic hyperglycemia contributes to the development of both macro- and microvascular conditions through a variety of metabolic pathways. Thus, it can cause a variety of metabolic and hemodynamic conditions, including upregulated advanced glycation end-products (AGEs) synthesis. In our previous study, the most abundant type of toxic AGEs (TAGE); i.e., glyceraldehyde-derived AGEs, were found to make a significant contribution to the pathogenesis of DM-induced angiopathy. Furthermore, accumulating evidence suggests that the binding of TAGE with their receptor (RAGE) induces oxidative damage, promotes inflammation, and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells. All of these effects could facilitate the pathogenesis of hypertension, cancer, diabetic vascular complications, CVD, dementia, and NASH. Thus, inhibiting TAGE synthesis, preventing TAGE from binding to RAGE, and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH. Here, we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH.
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Takeuchi M, Takino JI, Sakasai-Sakai A, Takata T, Ueda T, Tsutsumi M, Hyogo H, Yamagishi SI. Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies. World J Hepatol 2014. [PMID: 25544875 DOI: 10.4254/wjh.6.i12.880] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease around the world. It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and can lead to fibrosis, cirrhosis, liver failure, and/or hepatocellular carcinoma. NAFLD is also associated with other medical conditions such as obesity, diabetes mellitus (DM), metabolic syndrome, hypertension, insulin resistance, hyperlipidemia, and cardiovascular disease (CVD). In diabetes, chronic hyperglycemia contributes to the development of both macro- and microvascular conditions through a variety of metabolic pathways. Thus, it can cause a variety of metabolic and hemodynamic conditions, including upregulated advanced glycation end-products (AGEs) synthesis. In our previous study, the most abundant type of toxic AGEs (TAGE); i.e., glyceraldehyde-derived AGEs, were found to make a significant contribution to the pathogenesis of DM-induced angiopathy. Furthermore, accumulating evidence suggests that the binding of TAGE with their receptor (RAGE) induces oxidative damage, promotes inflammation, and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells. All of these effects could facilitate the pathogenesis of hypertension, cancer, diabetic vascular complications, CVD, dementia, and NASH. Thus, inhibiting TAGE synthesis, preventing TAGE from binding to RAGE, and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH. Here, we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH.
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Affiliation(s)
- Masayoshi Takeuchi
- Masayoshi Takeuchi, Akiko Sakasai-Sakai, Takanobu Takata, Tadashi Ueda, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan
| | - Jun-Ichi Takino
- Masayoshi Takeuchi, Akiko Sakasai-Sakai, Takanobu Takata, Tadashi Ueda, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan
| | - Akiko Sakasai-Sakai
- Masayoshi Takeuchi, Akiko Sakasai-Sakai, Takanobu Takata, Tadashi Ueda, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan
| | - Takanobu Takata
- Masayoshi Takeuchi, Akiko Sakasai-Sakai, Takanobu Takata, Tadashi Ueda, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan
| | - Tadashi Ueda
- Masayoshi Takeuchi, Akiko Sakasai-Sakai, Takanobu Takata, Tadashi Ueda, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan
| | - Mikihiro Tsutsumi
- Masayoshi Takeuchi, Akiko Sakasai-Sakai, Takanobu Takata, Tadashi Ueda, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan
| | - Hideyuki Hyogo
- Masayoshi Takeuchi, Akiko Sakasai-Sakai, Takanobu Takata, Tadashi Ueda, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan
| | - Sho-Ichi Yamagishi
- Masayoshi Takeuchi, Akiko Sakasai-Sakai, Takanobu Takata, Tadashi Ueda, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan
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Huang PH, Chen JW, Lin SJ. Effects of Cardiovascular Risk Factors on Endothelial Progenitor Cell. ACTA CARDIOLOGICA SINICA 2014; 30:375-381. [PMID: 27122814 PMCID: PMC4834954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Accepted: 03/10/2014] [Indexed: 06/05/2023]
Abstract
UNLABELLED Atherosclerosis is a systemic inflammatory disease of arterial wall and initiated by endothelial damage. The integrity and functional activity of endothelial monolayer play an important role in atherogenesis. The extent of endothelial injury may represent a balance between the magnitude of injury and the capacity for repair. Traditional view suggested endothelium integrity is maintained by neighboring mature endothelial cells which migrate and proliferate to restore the injured endothelial cells. However, a series of clinical and basic studies prompted by the discovery of bone marrow-derived endothelial progenitor cells (EPCs) have demonstrated that the injured endothelial monolayer may be regenerated partly by circulating EPCs. These circulating EPCs are mobilized endogenously triggered by tissue ischemia or exogenously by cytokine stimulation. Clinical studies demonstrated that levels of circulating EPCs are associated with vascular endothelial function and cardiovascular risk factors, and help to identify patients at increased cardiovascular risk. Reduced levels of circulating EPCs independently predict atherosclerotic disease progression and development of cardiovascular events. Therefore, a better understanding of the relation between EPCs and atherosclerosis would provide additional insight into the pathogenesis of cardiovascular disease and create novel therapeutic strategies. Here, we will make a brief review to clarify the effects of cardiovascular risk factors on circulating EPCs. KEY WORDS Atherosclerosis; endothelial function; endothelial progenitor cell.
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Affiliation(s)
- Po-Hsun Huang
- Division of Cardiology, Department of Medicine
- Institute of Clinical Medicine
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Jaw-Wen Chen
- Division of Cardiology, Department of Medicine
- Department of Medical Research, Taipei Veterans General Hospital
- Institute and Department of Pharmacology
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Shing-Jong Lin
- Division of Cardiology, Department of Medicine
- Department of Medical Research, Taipei Veterans General Hospital
- Institute of Clinical Medicine
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
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30
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The impact of endothelial progenitor cells on restenosis after percutaneous angioplasty of hemodialysis vascular access. PLoS One 2014; 9:e101058. [PMID: 24964143 PMCID: PMC4071067 DOI: 10.1371/journal.pone.0101058] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Accepted: 06/03/2014] [Indexed: 11/20/2022] Open
Abstract
Objective We prospectively investigate the relation between baseline circulating endothelial progenitor cells and the subsequent development of restenosis after angioplasty of hemodialysis vascular access. Background Effect of angioplasty for hemodialysis vascular access is greatly attenuated by early and frequent restenosis. Circulating endothelial progenitor cells (EPCs) play a key role in vascular repair but are deficient in hemodialysis patients. Method After excluding 14 patients due to arterial stenosis, central vein stenosis, and failed angioplasty, 130 patients undergoing angioplasty for dysfunctional vascular access were prospectively enrolled. Flow cytometry with quantification of EPC markers (defined as CD34+, CD34+KDR+, CD34+KDR+CD133+) in peripheral blood immediately before angioplasty procedures was used to assess circulating EPC numbers. Patients were followed clinically for up to one year after angioplasty. Results During the one-year follow-up, 95 patients (73%) received interventions for recurrent access dysfunction. Patients in the lower tertile of CD34+KDR+ cell count had the highest restenosis rates (46%) at three month (early restenosis), compared with patients in the medium and upper tertiles of CD34+KDR+ cell count (27% and 12% respectively, p = 0.002). Patients in the lower tertile of CD34+KDR+ cell count received more re-interventions during one year. Patients with early restenosis had impaired EPC adhesive function and increased senescence and apoptosis. In multivariate analysis, the CD34+KDR+ and CD34+KDR+CD133+ cell counts were independent predictors of target-lesion early restenosis. Conclusion Our results suggest that the deficiency of circulating EPCs is associated with early and frequent restenosis after angioplasty of hemodialysis vascular access.
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Suzuki R, Fukuda N, Katakawa M, Tsunemi A, Tahira Y, Matsumoto T, Ueno T, Soma M. Effects of an angiotensin II receptor blocker on the impaired function of endothelial progenitor cells in patients with essential hypertension. Am J Hypertens 2014; 27:695-701. [PMID: 24200748 DOI: 10.1093/ajh/hpt208] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Endothelial progenitor cells (EPCs) induce neovascularization and repair vascular damage. We have demonstrated that EPC function is impaired in hypertensive rats with increases in oxidative stress and that angiotensin II receptor blockers improved the impaired function of EPCs. In this study, we investigated basal EPC functions in normotensive control subjects and patients with essential hypertension and the effect of losartan on EPC function in hypertensive patients. METHODS Eighteen normotensive control subjects and 36 patients with essential hypertension who were undergoing treatment participated in the study. Hypertensive patients were randomly selected to receive 50mg of losartan or 4 mg of trichlormethiazide daily for 4 weeks. Peripheral blood mononuclear cells were isolated and cultured to assay EPC colony formation. Blood pressure, biological examination, and oxidative stress were evaluated in all subjects. RESULTS The number of EPC colonies was significantly lower in patients with essential hypertension than in normotensive control subjects. EPC colony number was significantly and inversely correlated with systolic and diastolic blood pressure in all subjects. EPC colony number was significantly increased by treatment with losartan in patients with essential hypertension but not affected by treatment with trichlormethiazide. CONCLUSIONS EPC function was inversely correlated with blood pressure and was impaired in essential hypertension. Losartan significantly improved the impaired EPC function in hypertensive patients. Impaired EPC function may determine the cardiovascular complications in essential hypertension. The improvement of EPC function with the administration of angiotensin II receptor blockers is considered to be one of the cardiovascular protective effects.
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Affiliation(s)
- Ryo Suzuki
- Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
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Chiang CH, Huang PH, Chiu CC, Hsu CY, Leu HB, Huang CC, Chen JW, Lin SJ. Reduction of circulating endothelial progenitor cell level is associated with contrast-induced nephropathy in patients undergoing percutaneous coronary and peripheral interventions. PLoS One 2014; 9:e89942. [PMID: 24646509 PMCID: PMC3960102 DOI: 10.1371/journal.pone.0089942] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 01/25/2014] [Indexed: 11/24/2022] Open
Abstract
Objectives Reduced number and impaired function of circulating endothelial progenitor cells (EPCs) in patients with chronic kidney disease have been reported. However, there is little data about the association between circulating EPC levels and risk of contrast-induced nephropathy (CIN). The aim of this study was to investigate the relationship between circulating EPCs and CIN in patients after angiography. Methods and Results A total of 77 consecutive patients undergoing elective percutaneous coronary intervention (PCI) and percutaneous transluminal angioplasty (PTA) were enrolled. Flow cytometry with quantification of EPC markers (defined as CD34+, CD34+KDR+, and CD34+KDR+CD133+) in peripheral blood samples was used to assess EPC number before the procedure. CIN was defined as an absolute increase ≧0.5 mg/dl or a relative increase ≧25% in the serum creatinine level at 48 hours after the procedure. Eighteen (24%) of the study subjects developed CIN. Circulating EPC levels were significantly lower in patients who developed CIN than in those without CIN (CD34+KDR+, 4.11±2.59 vs. 9.25±6.30 cells/105 events, P<0.001). The incidence of CIN was significantly greater in patients in the lowest EPC tertile (CD34+KDR+; from lowest to highest, 52%, 15%, and 4%, P<0.001). Using univariate logistic regression, circulating EPC number (CD34+KDR+) was a significant negative predictor for development of CIN (odds ratio 0.69, 95% CI 0.54–0.87, P = 0.002). Over a two-year follow-up, patients with CIN had a higher incidence of major adverse cardiovascular events including myocardial infarction, stroke, revascularization of treated vessels, and death (66.7% vs. 25.4%, P = 0.004) than did patients without CIN. Conclusions Decreased EPC level is associated with a greater risk of CIN, which may explain part of the pathophysiology of CIN and the poor prognosis in CIN patients.
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Affiliation(s)
- Chia-Hung Chiang
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Hsinchu Branch, Hsinchu, Taiwan
- Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Po-Hsun Huang
- Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
- * E-mail:
| | - Chun-Chih Chiu
- Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Chien-Yi Hsu
- Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Hsin-Bang Leu
- Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan
- Healthcare and Management Center, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Chin-Chou Huang
- Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
- Institute and Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Jaw-Wen Chen
- Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
- Institute and Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Shing-Jong Lin
- Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
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Cardiovascular disorders in the context of non-alcoholic Fatty liver disease: a literature review. J Tehran Heart Cent 2014; 9:1-8. [PMID: 25561963 PMCID: PMC4277785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 12/06/2013] [Indexed: 11/30/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the United States and other industrialized countries, and the reported prevalence in the developing countries is also rather high. This disease is associated with a high rate of morbidity and mortality and damage to the other organs. The cardiovascular system is, perhaps, the most vulnerable organ to NAFLD adverse effects to the extent that most mortality associated with this disease is reportedly from the cardiovascular system rather than from the liver itself. In this article, we review the significant aspects of cardiovascular disorders associated with NAFLD, including the epidemiology of cardiovascular diseases in NAFLD patients, factors that interfere in this relationship like hypertension, severity of NAFLD, and age of the patients, and finally preventive strategies whose employment could significantly improve the outcome.
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Mazzoccoli G, Tevy MF, Borghesan M, Delle Vergini MR, Vinciguerra M. Caloric restriction and aging stem cells: the stick and the carrot? Exp Gerontol 2013; 50:137-48. [PMID: 24211426 DOI: 10.1016/j.exger.2013.10.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 09/03/2013] [Accepted: 10/28/2013] [Indexed: 12/24/2022]
Abstract
Adult tissue stem cells have the ability to adjust to environmental changes and affect also the proliferation of neighboring cells, with important consequences on tissue maintenance and regeneration. Stem cell renewal and proliferation is strongly regulated during aging of the organism. Caloric restriction is the most powerful anti-aging strategy conserved throughout evolution in the animal kingdom. Recent studies relate the properties of caloric restriction to its ability in reprogramming stem-like cell states and in prolonging the capacity of stem cells to self-renew, proliferate, differentiate, and replace cells in several adult tissues. However this general paradigm presents with exceptions. The scope of this review is to highlight how caloric restriction impacts on diverse stem cell compartments and, by doing so, might differentially delay aging in the tissues of lower and higher organisms.
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Affiliation(s)
- Gianluigi Mazzoccoli
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, FG, Italy.
| | - Maria Florencia Tevy
- Genomics and Bioinformatics Centre, Major University of Santiago, Santiago, Chile
| | - Michela Borghesan
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, FG, Italy; University College London, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, London, United Kingdom
| | - Maria Rita Delle Vergini
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, FG, Italy
| | - Manlio Vinciguerra
- Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, FG, Italy; Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy; University College London, Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, London, United Kingdom.
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Gutiérrez-Grobe Y, Gavilanes-Espinar JG, Masso-Rojas FA, Sánchez-Valle V, Páez-Arenas A, Ponciano-Rodríguez G, Chávez-Tapia NC, Uribe M, Méndez-Sánchez N. Metabolic syndrome and nonalcoholic fatty liver disease. The role of endothelial progenitor cells. Ann Hepatol 2013; 12:908-914. [PMID: 24114821 DOI: 10.1016/s1665-2681(19)31296-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
BACKGROUND Endothelial dysfunction has been previously described in metabolic syndrome patients. The levels of circulating endothelial progenitor cells (EPCs) inversely correlates with the incidence of cardiovascular disease. The aim of this study was to investigate the association between NAFLD, metabolic syndrome and EPC levels. MATERIAL AND METHODS A cross-sectional pilot study was performed at a university hospital in Mexico. Two groups of patients without previously known chronic diseases were studied and classified according to the presence of NAFLD. Anthropometric, dietary, and biochemical variables, and circulating EPC number were measured and compared between the groups. RESULTS Forty subjects were included and classified into two groups: patients with NAFLD (n = 20) and a control group (n = 20). The overall prevalence of insulin resistance and metabolic syndrome was 25% and 17.5%, respectively. EPC levels were found to be higher in the NAFLD group (p < 0.05) as in the patients with insulin resistance (p < 0.01) and metabolic syndrome (p < 0.01). These levels showed correlation with the severity of steatosis. CONCLUSIONS Patients with NAFLD have increased levels of EPC, such levels are associated with the severity of NAFLD. These findings may suggest that these cells may play a role in the early natural history of NAFLD. EPC might be increased in an attempt to repair the endothelial damage resulting from metabolic alterations accompanying NAFLD. Further studies are needed to establish the dynamics of these cells in NAFLD.
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Tan A, Goh D, Farhatnia Y, G N, Lim J, Teoh SH, Rajadas J, Alavijeh MS, Seifalian AM. An anti-CD34 antibody-functionalized clinical-grade POSS-PCU nanocomposite polymer for cardiovascular stent coating applications: a preliminary assessment of endothelial progenitor cell capture and hemocompatibility. PLoS One 2013; 8:e77112. [PMID: 24116210 PMCID: PMC3793009 DOI: 10.1371/journal.pone.0077112] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 08/30/2013] [Indexed: 12/29/2022] Open
Abstract
In situ endothelialization of cardiovascular implants has emerged in recent years as an attractive means of targeting the persistent problems of thrombosis and intimal hyperplasia. This study aimed to investigate the efficacy of immobilizing anti-CD34 antibodies onto a POSS-PCU nanocomposite polymer surface to sequester endothelial progenitor cells (EPCs) from human blood, and to characterize the surface properties and hemocompatibility of this surface. Amine-functionalized fumed silica was used to covalently conjugate anti-CD34 to the polymer surface. Water contact angle, fluorescence microscopy, and scanning electron microscopy were used for surface characterization. Peripheral blood mononuclear cells (PBMCs) were seeded on modified and pristine POSS-PCU polymer films. After 7 days, adhered cells were immunostained for the expression of EPC and endothelial cell markers, and assessed for the formation of EPC colonies. Hemocompatibility was assessed by thromboelastography, and platelet activation and adhesion assays. The number of EPC colonies formed on anti-CD34-coated POSS-PCU surfaces was not significantly higher than that of POSS-PCU (5.0±1.0 vs. 1.7±0.6, p>0.05). However, antibody conjugation significantly improved hemocompatibility, as seen from the prolonged reaction and clotting times, decreased angle and maximum amplitude (p<0.05), as well as decreased platelet adhesion (76.8±7.8 vs. 8.4±0.7, p<0.05) and activation. Here, we demonstrate that POSS-PCU surface immobilized anti-CD34 antibodies selectively captured CD34+ cells from peripheral blood, although only a minority of these were EPCs. Nevertheless, antibody conjugation significantly improves the hemocompatibility of POSS-PCU, and should therefore continue to be explored in combination with other strategies to improve the specificity of EPC capture to promote in situ endothelialization.
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Affiliation(s)
- Aaron Tan
- Centre for Nanotechnology and Regenerative Medicine, UCL Division of Surgery & Interventional Science, University College London, London, United Kingdom
- UCL Medical School, University College London, London, United Kingdom
| | - Debbie Goh
- Centre for Nanotechnology and Regenerative Medicine, UCL Division of Surgery & Interventional Science, University College London, London, United Kingdom
- UCL Medical School, University College London, London, United Kingdom
| | - Yasmin Farhatnia
- Centre for Nanotechnology and Regenerative Medicine, UCL Division of Surgery & Interventional Science, University College London, London, United Kingdom
| | - Natasha G
- Centre for Nanotechnology and Regenerative Medicine, UCL Division of Surgery & Interventional Science, University College London, London, United Kingdom
- UCL Medical School, University College London, London, United Kingdom
| | - Jing Lim
- Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, Singapore
| | - Swee-Hin Teoh
- Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, Singapore
| | - Jayakumar Rajadas
- Biomaterials and Advanced Drug Delivery Laboratory, School of Medicine, Stanford University, Stanford, California, United States of America
| | | | - Alexander M. Seifalian
- Centre for Nanotechnology and Regenerative Medicine, UCL Division of Surgery & Interventional Science, University College London, London, United Kingdom
- Royal Free London NHS Foundation Trust, London, United Kingdom
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Hsu CY, Huang PH, Chiang CH, Leu HB, Huang CC, Chen JW, Lin SJ. Increased circulating endothelial apoptotic microparticle to endothelial progenitor cell ratio is associated with subsequent decline in glomerular filtration rate in hypertensive patients. PLoS One 2013; 8:e68644. [PMID: 23874701 PMCID: PMC3709900 DOI: 10.1371/journal.pone.0068644] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 05/31/2013] [Indexed: 02/07/2023] Open
Abstract
Background Recent research indicates hypertensive patients with microalbuminuria have decreased endothelial progenitor cells (EPCs) and increased levels of endothelial apoptotic microparticles (EMP). However, whether these changes are related to a subsequent decline in glomerular filtration rate (GFR) remains unclear. Methods and Results We enrolled totally 100 hypertensive out-patients with eGFR ≥30 mL/min/1.73 m2. The mean annual rate of GFR decline (△GFR/y) was −1.49±3.26 mL/min/1.73 m2 per year during the follow-up period (34±6 months). Flow cytometry was used to assess circulating EPC (CD34+/KDR+) and EMP levels (CD31+/annexin V+) in peripheral blood. The △GFR/y was correlated with the EMP to EPC ratio (r = −0.465, p<0.001), microalbuminuria (r = −0.329, p = 0.001), and the Framingham risk score (r = −0.245, p = 0.013). When we divided the patients into 4 groups according to the EMP to EPC ratio, there was an association between the EMP to EPC ratio and the ΔGFR/y (mean ΔGFR/y: 0.08±3.04 vs. −0.50±2.84 vs. −1.25±2.49 vs. −4.42±2.82, p<0.001). Multivariate analysis indicated that increased EMP to EPC ratio is an independent predictor of ΔeGFR/y. Conclusions An increased circulating EMP to EPC ratio is associated with subsequent decline in GFR in hypertensive patients, which suggests endothelial damage with reduced vascular repair capacity may contribute to further deterioration of renal function in patients with hypertension.
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Affiliation(s)
- Chien-Yi Hsu
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Po-Hsun Huang
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
- * E-mail:
| | - Chia-Hung Chiang
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Hsin-Bang Leu
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Healthcare and Management Center, Taipei Veterans General Hospital, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Chin-Chou Huang
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
- Institute and Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Jaw-Wen Chen
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
- Institute and Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Shing-Jong Lin
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
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Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A. Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients 2013; 5:1544-60. [PMID: 23666091 PMCID: PMC3708335 DOI: 10.3390/nu5051544] [Citation(s) in RCA: 605] [Impact Index Per Article: 50.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 04/12/2013] [Accepted: 04/16/2013] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease is marked by hepatic fat accumulation not due to alcohol abuse. Several studies have demonstrated that NAFLD is associated with insulin resistance leading to a resistance in the antilipolytic effect of insulin in the adipose tissue with an increase of free fatty acids (FFAs). The increase of FFAs induces mitochondrial dysfunction and development of lipotoxicity. Moreover, in subjects with NAFLD, ectopic fat also accumulates as cardiac and pancreatic fat. In this review we analyzed the mechanisms that relate NAFLD with metabolic syndrome and dyslipidemia and its association with the development and progression of cardiovascular disease.
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Affiliation(s)
- Melania Gaggini
- Institute of Clinical Physiology National Research Council, Pisa 56100, Italy; E-Mails: (M.G.); (M.M.); (E.B.)
| | - Mariangela Morelli
- Institute of Clinical Physiology National Research Council, Pisa 56100, Italy; E-Mails: (M.G.); (M.M.); (E.B.)
| | - Emma Buzzigoli
- Institute of Clinical Physiology National Research Council, Pisa 56100, Italy; E-Mails: (M.G.); (M.M.); (E.B.)
| | - Ralph A. DeFronzo
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX 78229, USA; E-Mail:
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastro-Hepatology, San Giovanni Battista Hospital, University of Turin, Turin 10126, Italy; E-Mail:
| | - Amalia Gastaldelli
- Institute of Clinical Physiology National Research Council, Pisa 56100, Italy; E-Mails: (M.G.); (M.M.); (E.B.)
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX 78229, USA; E-Mail:
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +39-050-315-2680/79; Fax: +39-050-315-2166
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Long J, Wang S, Zhang Y, Liu X, Zhang H, Wang S. The therapeutic effect of vascular endothelial growth factor gene- or heme oxygenase-1 gene-modified endothelial progenitor cells on neovascularization of rat hindlimb ischemia model. J Vasc Surg 2013; 58:756-65.e2. [PMID: 23562340 DOI: 10.1016/j.jvs.2012.11.096] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2012] [Revised: 11/21/2012] [Accepted: 11/25/2012] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To explore the therapeutic potential of endothelial progenitor cells (EPCs) transfected with vascular endothelial growth factor A (VEGFA) and heme oxygenase-1 (HO-1) on rat hindlimb ischemia model. METHODS Eukaryotic expression vectors encoding VEGFA or HO-1 were constructed and introduced into EPCs isolated from rat bone marrow. In total, 150 Sprague Dawley rat hindlimb ischemia models were established and randomized into five groups which were injected via tail vein with phosphate-buffered saline (PBS), nontransfected EPCs, VEGFA-modified EPCs, HO-1-modified EPCs, and both VEGFA- and HO-1-modified EPCs, respectively. The microvessel density, the expressions of VEGFA and HO-1 in the ischemic limbs, the recovery of blood flow as evaluated by laser-Doppler perfusion imaging, and the rate of limb salvage were compared among different groups. RESULTS Transplantation of both VEGFA- and HO-1-modified EPCs in recipient rats significantly increased the microvessel density (expressed as capillaries/m(2) at day 21 after operation, group vascular endothelial growth factor (VEGF)+HO-1, 357 ± 14.1; group VEGF, 253.7 ± 9.9; group HO-1, 255.5 ± 12.5; group EPC, 210.7 ± 10.3; group PBS, 144.3 ± 9.3; P < .001), the expressions of VEGFA and HO-1 in ischemic tissue, the recovery of blood flow (at day 21, VEGF+HO-1 group, 85.4 ± 17.8%; VEGF group, 51.2 ± 13.2%; HO-1 group, 50.4 ± 12.9%; EPC group, 39.9 ± 8.5%; PBS group, 28.3 ± 7.8%; P < .001), and the rate of limb salvage (VEGF+HO-1 group, 94.4%; VEGF group or HO-1 group, 63.6%; EPC group, 50.0%; PBS group, 11.1%), compared with transplantation of either VEGFA- or HO-1-modified EPCs alone, or of nontransfected EPCs, or PBS injection. The order of therapeutic effectiveness on ischemic limbs was VEGFA- + HO-1-modifed EPC > either VEGFA- or HO-1-modified EPC alone > nontransfected EPC > PBS. CONCLUSIONS VEGFA-modified EPC and HO-1-modified EPC synergized with each other in promoting angiogenesis in ischemic limbs of rat hindlimb ischemia model. In addition to VEGF, the introduction of HO-1 in EPC-based transplantation may serve as a novel and useful therapeutic strategy for ischemic disease of lower extremity.
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Affiliation(s)
- Jianting Long
- Department of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
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Apolipoprotein A-I mimetic peptide reverse D-4F improves the biological functions of mouse bone marrow-derived late EPCs via PI3K/AKT/eNOS pathway. Mol Cell Biochem 2013; 377:229-36. [DOI: 10.1007/s11010-013-1592-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 02/08/2013] [Indexed: 12/23/2022]
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Berger S, Aronson D, Lavie P, Lavie L. Endothelial Progenitor Cells in Acute Myocardial Infarction and Sleep-disordered Breathing. Am J Respir Crit Care Med 2013; 187:90-8. [DOI: 10.1164/rccm.201206-1144oc] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition, which is strongly associated with obesity and diabetes. The risk of cardiovascular disease is increased in NAFLD and represents the main cause of death in these patients. However, given the shared features between NAFLD, the metabolic syndrome and traditional cardiovascular risk factors, uncertainty exists as to whether NAFLD is an independent risk factor for increased cardiovascular disease. RECENT FINDINGS Multiple epidemiological and case-control studies now demonstrate that NAFLD is associated with increased vascular risk, independently of conventional cardiometabolic risk factors. Evidence also suggests a graded association between NAFLD severity and increased vascular risk. However, given the heterogeneous disease spectrum of NAFLD, these findings have limitations with respect to accuracy of diagnosis and staging of NAFLD in most studies. SUMMARY Although accumulating evidence points to NAFLD emerging as a novel cardiovascular risk factor, more research is needed to find suitable noninvasive biomarkers of NAFLD severity to allow better risk-stratification based on cardiovascular outcomes. Furthermore, with no established pharmacological treatment option for NAFLD currently available, any potential treatment must show efficacy not only in slowing liver disease progression, but also in ameliorating adverse cardiovascular outcomes.
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