|
1
|
Sommer P, Schreinlechner M, Noflatscher M, Engl C, Lener D, Theurl M, Kirchmair R, Marschang P. Hepatocyte growth factor as indicator for subclinical atherosclerosis. VASA 2024; 53:120-128. [PMID: 38205733 DOI: 10.1024/0301-1526/a001111] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2024]
Abstract
Background: Hepatocyte growth factor (HGF) is a pleiotropic cytokine mainly produced by mesenchymal cells. After endothelial damage by oxidized low-density lipoprotein (LDL), HGF is produced and released into the circulation in response. Due to this mechanism HGF has been proposed as possible clinical biomarker for clinical as well as subclinical atherosclerosis. Patients and methods: The conducted study is an observational, single centre, cohort study, including 171 patients with at least one cardiovascular risk factor or already established cardiovascular disease (CVD). Each patient underwent 3D plaque volumetry of the carotid and femoral arteries as well as physical examination and record of the medical history. Additionally, plasma HGF and further laboratory parameters like high sensitivity C-reactive protein and LDL-cholesterol were determined. Results: 169 patients were available for statistical analysis. In bivariate correlation, HGF showed a highly significant correlation with total plaque volume (TPV, r=0.48; p<0.001). In receiver operating characteristic (ROC) analysis for high TPV, HGF showed an area under the curve (AUC) of 0.68 (CI 95%: 0.59-0.77, p<0.001) with a sensitivity of 78% and a specificity of 52% to predict high TPV at a cut-off of 959 ng/ml. In the ROC-analysis for the presence of CVD, HGF demonstrated an AUC of 0.65 (95% CI 0.55-0.73; p=0.01) with a sensitivity of 77% and a specificity of 52%. Conclusions: Higher plasma levels of HGF are associated with higher atherosclerotic plaque volume as measured by 3D-ultrasound.
Collapse
Affiliation(s)
- Philip Sommer
- Department of Internal Medicine III (Cardiology and Angiology), Medical University of Innsbruck, Austria
- Department of Internal Medicine I (Cardiology, Angiology and Pulmology), Klinikum rechts der Isar, Technical University Munich, Germany
| | - Michael Schreinlechner
- Department of Internal Medicine III (Cardiology and Angiology), Medical University of Innsbruck, Austria
| | - Maria Noflatscher
- Department of Internal Medicine III (Cardiology and Angiology), Medical University of Innsbruck, Austria
| | - Clarisse Engl
- Department of Immunology, University of Pittsburgh, The Assembly, Pittsburgh, PA, USA
| | - Daniela Lener
- Department of Internal Medicine III (Cardiology and Angiology), Medical University of Innsbruck, Austria
| | - Markus Theurl
- Department of Internal Medicine III (Cardiology and Angiology), Medical University of Innsbruck, Austria
| | - Rudolf Kirchmair
- Department of Internal Medicine III (Cardiology and Angiology), Medical University of Innsbruck, Austria
| | - Peter Marschang
- Department of Internal Medicine III (Cardiology and Angiology), Medical University of Innsbruck, Austria
- Department of Internal Medicine, Central Hospital of Bolzano (SADES-ASDAA), Teaching Hospital of Paracelsus Medical University (PMU), Bolzano, Italy
| |
Collapse
|
|
2
|
Al-Ahmar I, Mohamed N, Elshony H. Paradoxical role of hepatocyte growth factor in ischemic stroke: stroke risk/stroke recovery. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2021. [DOI: 10.1186/s41983-021-00364-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hepatocyte growth factor (HGF) has an obvious pathological role in atherosclerosis and plaque instability leading to an acute ischemic stroke; however, its beneficial role in stroke recovery is still restricted to experimental studies. The aim of the current study was to investigate the association between HGF and carotid atherosclerosis and evaluate its value as a prognostic marker of ischemic stroke and its role in stroke recovery.
Results
This case–control study was done on 100 patients with first time anterior circulation ischemic stroke, subjected to clinical and laboratory evaluation of atherosclerosis risk factors. Brain imaging, cardiac work-up and ultrasonographic assessment of carotid atherosclerosis (using intimal medial thickness and plaque score) were all done. Clinical evaluation of initial stroke severity, using National Institutes of Health Stroke Scale (NIHSS), and stroke outcome after 3 m, using Modified Rankin Scale (MRS), was performed. Measurement of HGF serum concentration was done to all stroke patients within 24 h of stroke onset and compared to results of 100 matched healthy subjects aged more than 50 years. HGF was significantly higher in stroke patients than healthy controls and in atherothrombotic than cardioembolic stroke group and its level was significantly correlated with atherosclerosis risk factors, degree of carotid atherosclerosis and better stroke outcome; however, it was not significantly correlated with initial stroke severity.
Conclusion
HGF is strongly associated with carotid atherosclerosis and other atherosclerosis risk factors and subsequent atherothrombotic stroke. Also, it can be used as a good prognostic marker in atherothrombotic stroke suggesting its role in stroke recovery but more studies are needed to explore this beneficial role as well as its therapeutic potentials in ischemic stroke patients.
Collapse
|
|
3
|
Patel V, Dwivedi AK, Deodhar S, Mishra I, Cistola DP. Aptamer-based search for correlates of plasma and serum water T 2: implications for early metabolic dysregulation and metabolic syndrome. Biomark Res 2018; 6:28. [PMID: 30237882 PMCID: PMC6142358 DOI: 10.1186/s40364-018-0143-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 08/29/2018] [Indexed: 12/13/2022] Open
Abstract
Background Metabolic syndrome is a cluster of abnormalities that increases the risk for type 2 diabetes and atherosclerosis. Plasma and serum water T2 from benchtop nuclear magnetic resonance relaxometry are early, global and practical biomarkers for metabolic syndrome and its underlying abnormalities. In a prior study, water T2 was analyzed against ~ 130 strategically selected proteins and metabolites to identify associations with insulin resistance, inflammation and dyslipidemia. In the current study, the analysis was broadened ten-fold using a modified aptamer (SOMAmer) library, enabling an unbiased search for new proteins correlated with water T2 and thus, metabolic health. Methods Water T2 measurements were recorded using fasting plasma and serum from non-diabetic human subjects. In parallel, plasma samples were analyzed using a SOMAscan assay that employed modified DNA aptamers to determine the relative concentrations of 1310 proteins. A multi-step statistical analysis was performed to identify the biomarkers most predictive of water T2. The steps included Spearman rank correlation, followed by principal components analysis with variable clustering, random forests for biomarker selection, and regression trees for biomarker ranking. Results The multi-step analysis unveiled five new proteins most predictive of water T2: hepatocyte growth factor, receptor tyrosine kinase FLT3, bone sialoprotein 2, glucokinase regulatory protein and endothelial cell-specific molecule 1. Three of the five strongest predictors of water T2 have been previously implicated in cardiometabolic diseases. Hepatocyte growth factor has been associated with incident type 2 diabetes, and endothelial cell specific molecule 1, with atherosclerosis in subjects with diabetes. Glucokinase regulatory protein plays a critical role in hepatic glucose uptake and metabolism and is a drug target for type 2 diabetes. By contrast, receptor tyrosine kinase FLT3 and bone sialoprotein 2 have not been previously associated with metabolic conditions. In addition to the five most predictive biomarkers, the analysis unveiled other strong correlates of water T2 that would not have been identified in a hypothesis-driven biomarker search. Conclusions The identification of new proteins associated with water T2 demonstrates the value of this approach to biomarker discovery. It provides new insights into the metabolic significance of water T2 and the pathophysiology of metabolic syndrome. Electronic supplementary material The online version of this article (10.1186/s40364-018-0143-x) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Vipulkumar Patel
- 1Nanoparticle Diagnostics Laboratory, Institute for Cardiovascular & Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX 76107 USA.,2Center of Emphasis in Diabetes & Metabolism, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905 USA
| | - Alok K Dwivedi
- 3Division of Biostatistics & Epidemiology, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905 USA
| | - Sneha Deodhar
- 1Nanoparticle Diagnostics Laboratory, Institute for Cardiovascular & Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX 76107 USA
| | - Ina Mishra
- 1Nanoparticle Diagnostics Laboratory, Institute for Cardiovascular & Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX 76107 USA.,2Center of Emphasis in Diabetes & Metabolism, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905 USA
| | - David P Cistola
- 1Nanoparticle Diagnostics Laboratory, Institute for Cardiovascular & Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX 76107 USA.,2Center of Emphasis in Diabetes & Metabolism, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905 USA
| |
Collapse
|
|
4
|
Bielinski SJ, Berardi C, Decker PA, Larson NB, Bell EJ, Pankow JS, Sale MM, Tang W, Hanson NQ, Wassel CL, de Andrade M, Budoff MJ, Polak JF, Sicotte H, Tsai MY. Hepatocyte growth factor demonstrates racial heterogeneity as a biomarker for coronary heart disease. Heart 2017; 103:1185-1193. [PMID: 28572400 DOI: 10.1136/heartjnl-2016-310450] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 01/19/2017] [Accepted: 01/27/2017] [Indexed: 11/03/2022] Open
Abstract
OBJECTIVE To determine if hepatocyte growth factor (HGF), a promising biomarker of coronary heart disease (CHD) given its release into circulation in response to endothelial damage, is associated with subclinical and clinical CHD in a racial/ethnic diverse population. METHODS HGF was measured in 6738 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Highest mean HGF values (pg/mL) were observed in Hispanic, followed by African, non-Hispanic white, then Chinese Americans. RESULTS In all races/ethnicities, HGF levels were associated with older age, higher systolic blood pressure (SBP) and body mass index, lower high-density lipoprotein, diabetes and current smoking. In fully adjusted models, each SD higher HGF was associated with an average increase in coronary artery calcium (CAC) of 55 Agatston units for non-Hispanic whites (p<0.001) and 51 Agatston units for African-Americans (p=0.007) but was not in the other race/ethnic groups (interaction p=0.02). There were 529 incident CHD events, and CHD risk was 41% higher in African (p<0.001), 17% in non-Hispanic white (p=0.026) and Chinese (p=0.36), and 6% in Hispanic Americans (p=0.56) per SD increase in HGF. CONCLUSION In a large and diverse population-based cohort, we report that HGF is associated with subclinical and incident CHD. We demonstrate evidence of racial/ethnic heterogeneity within these associations, as the results are most compelling in African-Americans and non-Hispanic white Americans. We provide evidence that HGF is a biomarker of atherosclerotic disease that is independent of traditional risk factors.
Collapse
Affiliation(s)
- Suzette J Bielinski
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Cecilia Berardi
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.,Department of Internal Medicine, Albert Einstein College of Medicine, and Montefiore Medical Center, Bronx, New York, USA
| | - Paul A Decker
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Nicholas B Larson
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Elizabeth J Bell
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - James S Pankow
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Michele M Sale
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
| | - Weihong Tang
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Naomi Q Hanson
- Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Christina L Wassel
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Colchester, Vermont, USA
| | - Mariza de Andrade
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Matthew J Budoff
- Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, California, USA
| | - Joseph F Polak
- Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Hugues Sicotte
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Y Tsai
- Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
| |
Collapse
|
|
5
|
Oliva-Olivera W, Lhamyani S, Coín-Aragüez L, Castellano-Castillo D, Alcaide-Torres J, Yubero-Serrano EM, El Bekay R, Tinahones FJ. Neovascular deterioration, impaired NADPH oxidase and inflammatory cytokine expression in adipose-derived multipotent cells from subjects with metabolic syndrome. Metabolism 2017; 71:132-143. [PMID: 28521866 DOI: 10.1016/j.metabol.2017.03.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 02/24/2017] [Accepted: 03/23/2017] [Indexed: 01/09/2023]
Abstract
OBJECTIVE Expansion of adipose tissue depends on the growth of its vascular network and it has been shown that adipose tissue dysfunction in obese subjects with the metabolic syndrome is associated with decreased angiogenesis. However, some subjects with a high body mass index do not develop metabolic abnormalities associated with obesity. In this study we examined the neovascular properties, expression levels of proteins involved in cellular redox balance and inflammatory cytokines in adipose-derived multipotent mesenchymal cells (ASCs) of subjects with different metabolic profiles. MATERIALS/METHODS We applied cell culture, flow cytometry, RT-qPCR and ELISA techniques to characterize the ASCs isolated from paired biopsies of visceral (visASCs) and subcutaneous (subASCs) adipose tissue from 39 subjects grouped into normal weight (Nw), obese without metabolic syndrome (NonMS) and with metabolic syndrome (MS). RESULTS VisASCs and subASCs from MS subjects showed a decrease in tubules formation capacity compared to ASCs from NonMS subjects as well as changes in the expression levels of proteins involved in cell redox balance and secretion levels of proteins linked to the senescence-associated secretory phenotype. Deterioration in the neovascular properties of subASCs from the MS subjects was also evident in the decreased levels of VEGF secretion during adipogenesis and in the effects of the conditioned medium on endothelial cell tubule formation. CONCLUSIONS Our findings suggest a redox imbalance status in ASCs from subjects with metabolic syndrome and decreased their neovascular function that probably contributes to the vascular insufficiency of adipose depots.
Collapse
Affiliation(s)
- Wilfredo Oliva-Olivera
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain; CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Spain.
| | - Said Lhamyani
- Research Laboratory, Science School, University of Málaga (UMA), Campus Teatinos s/n, 29010 Málaga, Spain
| | - Leticia Coín-Aragüez
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain; CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Spain
| | - Daniel Castellano-Castillo
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain; CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Spain
| | - Juan Alcaide-Torres
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain; CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Spain
| | - Elena María Yubero-Serrano
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain; Lipids and Atherosclerosis Unit, Maimonides Institute of Biomedical Research of Córdoba, Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain
| | - Rajaa El Bekay
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain; CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Spain.
| | - Francisco José Tinahones
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain; CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Spain.
| |
Collapse
|
|
6
|
Libetta C, Esposito P, Martinelli C, Grosjean F, Gregorini M, Rampino T, Dal Canton A. Hepatocyte growth factor (HGF) and hemodialysis: physiopathology and clinical implications. Clin Exp Nephrol 2016; 20:371-378. [PMID: 26676905 DOI: 10.1007/s10157-015-1211-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 12/02/2015] [Indexed: 02/07/2023]
Abstract
Hepatocyte growth factor (HGF) is a pleiotropic cytokine which exerts a variety of effects on several cells, being involved in the regulation of many biological processes, such as inflammation, tissue repair, morphogenesis, angiogenesis, tumour propagation, immunomodulation of viral infections and cardio-metabolic activities. Patients undergoing regular hemodialysis (HD) present elevated levels of HGF, mainly due to the leukocyte activation associated with HD treatment. High HGF levels might account for specific clinical features of HD patients, i.e. mild liver damage in course of HCV-infection and high cardiovascular risk profile. Moreover, in patients with acute kidney injury, the induction of HGF may represent a crucial step to promote renal recovery, which can have important prognostic consequences in the short and long-term. In this review we discuss the mechanisms underlying HGF production in HD patients, the role of HGF in this particular patient population and the potential clinical implications derived from the study of HGF in HD patients.
Collapse
Affiliation(s)
- Carmelo Libetta
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Piazzale Golgi 2, 27100, Pavia, Italy
| | - Pasquale Esposito
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Piazzale Golgi 2, 27100, Pavia, Italy.
| | - Claudia Martinelli
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Piazzale Golgi 2, 27100, Pavia, Italy
| | - Fabrizio Grosjean
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Piazzale Golgi 2, 27100, Pavia, Italy
| | - Marilena Gregorini
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Piazzale Golgi 2, 27100, Pavia, Italy
| | - Teresa Rampino
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Piazzale Golgi 2, 27100, Pavia, Italy
| | - Antonio Dal Canton
- Department of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Piazzale Golgi 2, 27100, Pavia, Italy
| |
Collapse
|
|
7
|
Dishi M, Hevner K, Qiu C, Fida NG, Abetew DF, Williams MA, Enquobahrie DA. Early Pregnancy Maternal Hepatocyte Growth Factor and Risk of Gestational Diabetes. BRITISH JOURNAL OF MEDICINE AND MEDICAL RESEARCH 2015; 9:BJMMR.18632. [PMID: 27158627 PMCID: PMC4856214 DOI: 10.9734/bjmmr/2015/18632] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
AIMS We investigated associations of serum hepatocyte growth factor (HGF) with risk of gestational diabetes mellitus (GDM). We also examined whether pre-pregnancy overweight/obesity status or leisure-time physical activity (LTPA) modify these associations. METHODS In a nested case-control study (173 GDM cases and 187 controls) among participants of a pregnancy cohort, early pregnancy (16 weeks of gestation, on average) serum HGF was measured using enzyme-linked immunoassay. GDM was diagnosed using American Diabetes Association guidelines. Logistic regression was used to calculate odd ratios (ORs) and 95% confidence intervals (CI). Effect modifications by pre-pregnancy overweight/obesity status or LTPA during pregnancy were examined using stratified analyses and interaction terms. RESULTS Overall, we did not find significant associations of serum HGF with GDM risk (p-value> 0.05). However, compared with women who had low serum HGF concentrations (<2.29 ng/ml), women with high serum HGF concentrations (≥ 2.29 ng/ml) had 3.8-fold (95%CI: 1.30-10.98) and 4.5-fold (95%CI: 1.28-15.80) higher GDM risk among women who were overweight/obese, pre-pregnancy (body mass index≥25 kg/m2), or did not report LTPA, respectively. These associations were not present among women who were not overweight/obese (interaction p=0.05) or reported LTPA (interaction p=0.05). CONCLUSION Overweight/obesity status and LTPA may modify associations of early pregnancy serum HGF with subsequent GDM risk.
Collapse
Affiliation(s)
- Michal Dishi
- Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, USA
| | - Karin Hevner
- Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, USA
| | - Chunfang Qiu
- Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, USA
| | - Neway G. Fida
- Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Dejene F. Abetew
- Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, USA
| | | | - Daniel A. Enquobahrie
- Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| |
Collapse
|
|
8
|
Konya H, Miuchi M, Satani K, Matsutani S, Yano Y, Tsunoda T, Ikawa T, Matsuo T, Ochi F, Kusunoki Y, Tokuda M, Katsuno T, Hamaguchi T, Miyagawa JI, Namba M. Asymmetric dimethylarginine, a biomarker of cardiovascular complications in diabetes mellitus. World J Exp Med 2015; 5:110-119. [PMID: 25992325 PMCID: PMC4436934 DOI: 10.5493/wjem.v5.i2.110] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Revised: 12/23/2014] [Accepted: 02/09/2015] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular (CV) complications are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis being a common risk factor for prospective crisis of coronary artery diseases and/or cerebral infarction in DM subjects. From another point of view, asymmetric dimethylarginine (ADMA) has been established as an inhibitor of endogenous nitric oxide synthesis and the relationship between ADMA and arteriosclerosis has been reported. In our study with 87 type 2 DM (T2DM) patients, we have examined whether ADMA and other CV risk factors are the useful predictors of DMCV complications. After the measurement of the respective CV risk factors, we have followed the enrolled T2DM patients for 5 years. We have finally analyzed 77 patients. DMCV complications developed in 15 cases newly within 5 years, and 4 cases recurred. The concentrations of ADMA in plasma were markedly more elevated in 19 DM patients with CV complications than in 58 DM patients without CV complications. Urinary albumin (U-Alb), mean intimal-medial thickness (IMT) and ankle brachial index (ABI) were also higher in patients with CV complications. Multiple regression analyses showed that U-Alb had an influence on the high level of ADMA (standardized β = 6.59, P = 0.00014) independently of age, systolic BP, fibrinogen, mean IMT, plaque score, and ABI. The review indicates what is presently known regarding plasma ADMA that might be a new and meaningful biomarker of CV complications in DM subjects.
Collapse
|
|
9
|
Baldeón R. L, Weigelt K, de Wit H, Ozcan B, van Oudenaren A, Sempértegui F, Sijbrands E, Grosse L, Freire W, Drexhage HA, Leenen PJM. Decreased serum level of miR-146a as sign of chronic inflammation in type 2 diabetic patients. PLoS One 2014; 9:e115209. [PMID: 25500583 PMCID: PMC4264887 DOI: 10.1371/journal.pone.0115209] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 11/19/2014] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND There is increasing evidence that chronic inflammation is an important determinant in insulin resistance and in the pathogenesis of type 2 diabetes (T2D). MicroRNAs constitute a newly discovered system of cell regulation and in particular two microRNAs (miR-146a and miR-155) have been described as regulators and biomarkers of inflammation. AIM To determine a putative association between the levels of miR-146a and miR-155 in serum of T2D patients, clinical parameters and serological indicators of inflammation. METHODS We performed quantitative Real Time PCR (qPCR) of microRNAs from serum (56 Ecuadorian T2D ambulatory patients and 40 non-diabetic controls). In addition, we evaluated T2D-related serum cytokines.chemokines and growth factors using a commercially available multi-analyte cytometric bead array system. We correlated outcomes to clinical parameters, including BMI, HbA1c and lipid state. RESULTS The Ecuadorian non-diabetic controls appeared as overweight (BMI>25: patients 85%, controls 82.5%) and as dyslipidemic (hypercholesterolemia: patients 60.7%, controls 67.5%) as the patients. The serum levels of miR-146a were significantly reduced in T2D patients as compared to these non-diabetic, but obese/dyslipidemic control group (mean patients 0.61, mean controls set at 1; p = 0.042), those of miR-155 were normal.The serum levels of both microRNAs correlated to each other (r = 0.478; p<0.001) and to leptin levels. The microRNAs did not correlate to BMI, glycemia and dyslipidemia.From the tested cytokines, chemokines and growth factors, we found IL-8 and HGF significantly raised in T2D patients versus non-diabetic controls (p = 0.011 and 0.023 respectively). CONCLUSIONS This study shows decreased serum anti-inflammatory miR-146a, increased pro-inflammatory IL-8 and increased HGF (a vascular/insular repair factor) as discriminating markers of failure of glucose control occurring on the background of obesity and dyslipidemia.
Collapse
Affiliation(s)
- Lucy Baldeón R.
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Immunology, Central University of Ecuador, Quito, Ecuador
| | - Karin Weigelt
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Harm de Wit
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Behiye Ozcan
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Adri van Oudenaren
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | | | - Eric Sijbrands
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Laura Grosse
- Department of Psychiatry, University of Münster, Münster, Germany
| | - Wilma Freire
- Institute of Research in Health and Nutrition, University San Francisco de Quito, Quito, Ecuador
| | - Hemmo A. Drexhage
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Prometeo Program SENESCYT, Central University of Ecuador and Universidad de las Fuerzas Armadas, Quito, Ecuador
| | - Pieter J. M. Leenen
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| |
Collapse
|
|
10
|
Konya H, Miuchi M, Satani K, Matsutani S, Tsunoda T, Yano Y, Katsuno T, Hamaguchi T, Miyagawa JI, Namba M. Hepatocyte growth factor, a biomarker of macroangiopathy in diabetes mellitus. World J Diabetes 2014; 5:678-688. [PMID: 25317245 PMCID: PMC4138591 DOI: 10.4239/wjd.v5.i5.678] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 03/01/2014] [Accepted: 06/03/2014] [Indexed: 02/05/2023] Open
Abstract
Atherosclerotic involvements are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis (CA) being a common risk-factor for prospective crisis of coronary artery diseases (CAD) and/or cerebral infarction (CI) in DM subjects. From another point of view, several reports have supplied augmenting proof that hepatocyte growth factor (HGF) has a physiopathological part in DM involvements. HGF has been a mesenchymal-derived polyphenic factor which modulates development, motion, and morphosis of diverse cells, and has been regarded as a humor intermediator of epithelial-mesenchymal interplays. The serum concentrations of HGF have been elevated in subjects with CAD and CI, especially during the acute phase of both disturbances. In our study with 89 type 2 DM patients, the association between serum concentrations of HGF and risk-factors for macrovascular complications inclusive of CA were examined. The average of serum HGF levels in the subjects was more elevated than the reference interval. The serum HGF concentrations associated positively with both intimal-media thickness (IMT) (r = 0.24, P = 0.0248) and plaque score (r = 0.27, P = 0.0126), indicating a relationship between the elevated HGF concentrations and advancement of CA involvements. Multivariate statistical analysis accentuated that serum concentrations of HGF would be associated independently with IMT (standardized = 0.28, P = 0.0499). The review indicates what is presently known regarding serum HGF might be a new and meaningful biomarker of macroangiopathy in DM subjects.
Collapse
|
|
11
|
Loudon JA. Two sides of the one coin-the cardiac and vascular system. Cardiovasc Drugs Ther 2013; 28:199-201. [PMID: 24281898 DOI: 10.1007/s10557-013-6505-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- John A Loudon
- Wetherill Park Medical Centre, Suite 101, Stockland Mall, Polding Street, Wetherill Park, Sydney, NSW, 2164, Australia,
| |
Collapse
|
|
12
|
Kochegura TN, Makarevich PI, Ovchinnikov AG, Zhigunova LV, Lahova EL, Shestakova MV, Ageev FT, Parfenova EV. Circulating hepatocyte growth factor (HGF) in patients with comorbidity of chronic heart failure, type 2 diabetes mellitus and impaired lipid metabolism. DIABETES MELLITUS 2013. [DOI: 10.14341/2072-0351-3752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
AIM: To evaluate the plasma level of circulating heptocyte growth factor (HGF) in patients with comorbidity of post-infarction chronic heart failure (CHF), type 2 diabetes mellitus (T2DM) and obesity. We also aimed to assess possible correlations between HGF levels and parameters of carbohydrate and lipid metabolism, as well as myocardial functional characteristics and classic biochemical severity markers for CHF.17Сахар ный диабет КардиологияСахарный диабет. 2013;(2):17-25
MATERIALS AND METHODS: We enrolled 100 patients for participation in this study, including the following subgroups: 20 individuals with- out cardiovascular and glycemic disorders, 30 patients with CHF, 25 patients with CHF/T2DM comorbidity and 25 diabetic patients with no signs of heart failure. Quantitative plasma HGF analysis was performed with enzyme-linked immunosorbent assay (ELISA).
RESULTS: Plasma HGF was elevated both in patients with CHF and T2DM as measured against healthy control group. The elevation was most prominent in patients with CHF/T2DM comorbidity and was found to correlate with HbA1c level (r=0.52, p=0.03). Plasma HGF also correlated with BMI (r=0.42, p=0007) in a unified study group, though we observed no statistically significant difference between subgroups with a trend toward higher HGF in obese patients with CHF/T2DM comorbidity (626.1?254.1 pg/ml vs 742.0?210.7 pg/ml respectively; p 0.05). Interestingly, plasma HGF was also significantly higher in controls with BMI 30 km/m2 (324.1?107.7 pg/ml vs 436.9?112.3 pg/ml, p=0.03).Circulating HGF correlated with plasma levels of N-terminal fragment of B-type natriuretic peptide (NT-proBNP) and such structural and functional myocardial characteristics as left atrial size and maximum volume along with left ventricular ejection fraction (EF), end-diastolic volume (EDV) and end-diastolic dimension (EDD).
CONCLUSION: These findings suggest that HGF may potentially serve as a prediction marker for unfavorable myocardial remodeling and poor prognosis in CHF patients with T2DM and obesity, though this possibility should be further investigated in follow-up studies.
Collapse
|
|
13
|
Kim JS, Kim IK, Lee SY, Song BW, Cha MJ, Song H, Choi E, Lim S, Ham O, Jang Y, Hwang KC. Anti-proliferative effect of rosiglitazone on angiotensin II-induced vascular smooth muscle cell proliferation is mediated by the mTOR pathway. Cell Biol Int 2012; 36:305-310. [PMID: 22050182 DOI: 10.1042/cbi20100524] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
VSMC (vascular smooth muscle cell) proliferation contributes significantly to intimal thickening in atherosclerosis, restenosis and venous bypass graft diseases. Ang II (angiotensin II) has been implicated in VSMC proliferation though the activation of multiple growth-promoting signals. Although TZDs (thiazolidinediones) can inhibit VSMC proliferation and reduce Ang II-induced fibrosis, the mechanism underlying the inhibition of VSMC proliferation and fibrosis needs elucidation. We have used primary cultured rat aortic VSMCs and specific antibodies to investigate the inhibitory mechanism of rosiglitazone on Ang II-induced VSMC proliferation. Rosiglitazone treatment significantly inhibited Ang II-induced rat aortic VSMC proliferation in a dose-dependent manner. Western blot analysis showed that rosiglitazone significantly lowered phosphorylated ERK1/2 (extracellular-signal-regulated kinase 1/2), Akt (also known as protein kinase B), mTOR (mammalian target of rapamycin), p70S6K (70 kDa S6 kinase) and 4EBP1 (eukaryotic initiation factor 4E-binding protein) levels in Ang II-treated VSMCs. In addition, PPAR-γ (peroxisome-proliferator-activated receptor γ) mRNA increased significantly and CTGF (connective tissue growth factor), Fn (fibronectin) and Col III (collagen III) levels decreased significantly. The results demonstrate that the rosiglitazone directly inhibits the pro-atherosclerotic effect of Ang II on rat aortic VSMCs. It also attenuates Ang II-induced ECM (extracellular matrix) molecules and CTGF production in rat aortic VSMCs, reducing fibrosis. Importantly, PPAR-γ activation mediates these effects, in part, through the mTOR-p70S6K and -4EBP1 system.
Collapse
Affiliation(s)
- Jung-Sun Kim
- Cardiology Division, Yonsei Cardiovascular Center, Yonsei University Health System, Seoul, South Korea
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Gu JH, Lee JS, Kim DW, Yoon ES, Dhong ES. Neovascular potential of adipose-derived stromal cells (ASCs) from diabetic patients. Wound Repair Regen 2012; 20:243-52. [DOI: 10.1111/j.1524-475x.2012.00765.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2011] [Accepted: 07/30/2011] [Indexed: 11/29/2022]
Affiliation(s)
- Ja Hea Gu
- Department of Plastic and Reconstructive Surgery; Korea University Guro Hospital; Guro-gu, Seoul; Korea
| | - Jae Sun Lee
- Medical Science Institute; Korea University Ansan Hospital; Danwon-gu, Ansan city, Gyeonggi-do; Korea
| | - Deok-Woo Kim
- Department of Plastic and Reconstructive Surgery, Korea University Ansan Hospital; Danwon-gu; Ansan city, Gyeonggi-do; Korea
| | - Eul-Sik Yoon
- Department of Plastic and Reconstructive Surgery, Korea University Ansan Hospital; Danwon-gu; Ansan city, Gyeonggi-do; Korea
| | - Eun-Sang Dhong
- Department of Plastic and Reconstructive Surgery, Korea University Ansan Hospital; Danwon-gu; Ansan city, Gyeonggi-do; Korea
| |
Collapse
|
|
15
|
Liu Y, Wang T, Yan J, Jiagbogu N, Heideman DA, Canfield AE, Alexander MY. HGF/c-Met signalling promotes Notch3 activation and human vascular smooth muscle cell osteogenic differentiation in vitro. Atherosclerosis 2011; 219:440-7. [PMID: 21920521 PMCID: PMC3925803 DOI: 10.1016/j.atherosclerosis.2011.08.033] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 07/21/2011] [Accepted: 08/18/2011] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Vascular calcification is a major clinical problem and elucidating the underlying mechanism is important to improve the prognosis of patients with cardiovascular disease. We aimed to elucidate the role and mechanism of action of Hepatocyte Growth Factor (HGF)/c-Met signalling in vascular calcification and establish whether blocking this pathway could prevent mineralisation of vascular smooth muscle cells (VSMCs) in vitro. METHODS AND RESULTS We demonstrate increased HGF secretion and c-Met up-regulation and phosphorylation during VSMC osteogenic differentiation. Adenoviral-mediated over-expression of HGF (AdHGF) in VSMCs accelerated mineralisation, shown by alizarin red staining, and significantly increased (45)Calcium incorporation (1.96 ± 0.54-fold [P < 0.05]) and alkaline phosphatase (ALP) activity (3.01 ± 0.8-fold [P < 0.05]) compared to controls. AdHGF also significantly elevated mRNA expression of bone-related proteins, Runx2, osteocalcin, BMP2 and osterix in VSMCs. AdHGF-accelerated mineralisation correlated with increased Akt phosphorylation, nuclear translocation of Notch3 intracellular domain (N3IC) and up-regulation of the Notch3 target protein, HES1. In contrast, adenoviral-mediated over-expression of the HGF antagonist, NK4, markedly attenuated VSMC mineralisation, and reduced c-Met phosphorylation, Akt activation and HES1 protein expression compared to AdHGF-treated cells. Furthermore, the Notch inhibitor, DAPT, attenuated N3IC nuclear translocation and AdHGF-induced mineralisation. CONCLUSION We demonstrate HGF induces VSMC osteogenic differentiation via c-Met/Akt/Notch3 signalling, highlighting these pathways as potential targets for intervention of vascular calcification.
Collapse
MESH Headings
- Adenoviridae/genetics
- Alkaline Phosphatase/metabolism
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Bone Morphogenetic Protein 2/genetics
- Calcium/metabolism
- Cell Differentiation
- Cells, Cultured
- Core Binding Factor Alpha 1 Subunit/genetics
- Genetic Vectors
- Hepatocyte Growth Factor/genetics
- Hepatocyte Growth Factor/metabolism
- Homeodomain Proteins/metabolism
- Humans
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Osteogenesis
- Phosphorylation
- Proto-Oncogene Proteins c-akt/metabolism
- Proto-Oncogene Proteins c-met/metabolism
- RNA, Messenger/metabolism
- Receptor, Notch3
- Receptors, Notch/metabolism
- Signal Transduction
- Sp7 Transcription Factor
- Time Factors
- Transcription Factor HES-1
- Transcription Factors/genetics
- Transfection
- Up-Regulation
- Vascular Calcification/genetics
- Vascular Calcification/metabolism
- Vascular Calcification/pathology
Collapse
Affiliation(s)
- Yiwen Liu
- Cardiovascular Research Group, University of Manchester, UK
| | - Tao Wang
- Medical Genetics Research Group, University of Manchester, UK
| | - Jianyun Yan
- Cardiovascular Research Group, University of Manchester, UK
| | - Naomi Jiagbogu
- Cardiovascular Research Group, University of Manchester, UK
| | | | - Ann E. Canfield
- Cardiovascular Research Group, University of Manchester, UK
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, UK
| | | |
Collapse
|
|
16
|
Abstract
Biomarkers for Diabetes Complications: The Results of Several Clinical StudiesDiabetes is a common metabolic disorder. Its microvascular and macrovascular complications contribute to death, disabilities, and reduction in life expectancy in diabetes. It is a costly disease, and affects not only the patient and family, but also the public health, communities and society. It takes an increasing proportion of the national health care expenditure. The prevention of the development of diabetes and its complications is a major concern. Biomarkers have been investigated for understanding the mechanisms of the development and progression of diabetic complications. In this paper, the biomarkers which are recommended in the clinical practice and laboratory medicine guidelines, and which have been investigated for prediction or diagnosis of diabetes complications, have been reviewed. The results of several clinical studies will be summarized.
Collapse
|
|
17
|
Prospective, randomized, single-blind comparison of effects of 6 months' treatment with atorvastatin versus pravastatin on leptin and angiogenic factors in patients with coronary artery disease. Heart Vessels 2011; 27:337-43. [PMID: 21643812 DOI: 10.1007/s00380-011-0156-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Accepted: 05/13/2011] [Indexed: 12/15/2022]
Abstract
Leptin has been reported to exert an atherosclerotic effect by regulating expression of angiogenic factors that have been implicated in the pathogenesis of coronary artery disease (CAD). The purpose of this study was to investigate whether lipid-lowering therapy (LLT) with statins could affect leptin levels and angiogenic factors in patients with CAD. This study included 76 patients with CAD and 15 subjects without CAD (non-CAD). CAD patients were randomized to 6 months of intensive LLT with atorvastatin or moderate LLT with pravastatin. Plasma leptin, angiopoetin-2 (Ang-2), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) levels were measured prior to statin therapy (baseline) and after 6 months. Baseline levels of leptin, Ang-2, HGF and VEGF were higher in the CAD group than in the non-CAD group (all P < 0.05). Treatment with intensive LLT decreased leptin, Ang-2, HGF and VEGF levels, whereas moderate LLT did not change these levels. This study suggests that LLT with atorvastatin decreases leptin levels and angiogenic factors in patients with CAD, possibly contributing to the beneficial effects of LLT with atorvastatin in CAD.
Collapse
|
|
18
|
Kadoglou NPE, Avgerinos ED, Liapis CD. An update on markers of carotid atherosclerosis in patients with Type 2 diabetes. Biomark Med 2010; 4:601-9. [DOI: 10.2217/bmm.10.79] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Carotid atherosclerosis constitutes an important cause of ischemic brain attack and stroke, accounting for up to 40% of cases of ischemic cerebrovascular disease. Type 2 diabetes mellitus is an independent risk factor for stroke and its recurrence. Thus, identifying diabetic patients who are at high risk of developing stroke is of great clinical importance. Noninvasive measurements of surrogate markers of atherosclerosis, such as novel serum biomarkers, can be helpful in detecting subclinical carotid disease, especially among individuals at the highest cardio-/cerebro-vascular risk. Previous studies have proposed an expanding body of serum biomarkers, such as C-reactive protein, fibrinogen, adipokines, cytokines and growth factors, as novel indicators of carotid atherosclerosis development that predict carotid-related clinical outcomes. Furthermore, those biomarkers are expected to assess the efficacy of both pharmaceutical and interventional strategies. Accordingly, it is increasingly clear that measuring biomarkers may improve the definition of cerebrovascular risk profile in patients with Type 2 diabetes mellitus.
Collapse
Affiliation(s)
| | - Efthimios D Avgerinos
- Department of Vascular Surgery, Attikon University Hospital, Medical School, Athens, Greece
| | - Christos D Liapis
- Department of Vascular Surgery, Attikon University Hospital, Medical School, Athens, Greece
| |
Collapse
|
|
19
|
Anan F, Masaki T, Jikumaru K, Iwao T, Eshima N, Saikawa T, Yoshimatsu H. Hepatocyte growth factor is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients. Eur J Clin Invest 2010; 40:585-90. [PMID: 20497462 DOI: 10.1111/j.1365-2362.2010.02301.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. Elevated hepatocyte growth factor (HGF) levels are associated with a high mortality rate in type 2 diabetic patients. The preliminary study was therefore designed to test the hypothesis that the presence of WML correlates with HGF and insulin resistance in type 2 diabetic patients not receiving insulin treatment. MATERIAL AND METHODS Based on brain magnetic resonance imaging, 92 type 2 diabetic patients were divided into two groups: WML-positive group (age 60 +/- 5 years, mean +/- SD, n = 35) and WML-negative group (age 59 +/- 6 years, mean +/- SD, n = 57. The level of blood glucose was assessed by fasting plasma glucose, fasting immunoreactive insulin, homeostasis model assessment (HOMA) index and haemoglobin A1c (HbA1c). RESULTS The body mass index was higher in the WML-positive group than that in the WML-negative group (P < 0.005). Plasma levels of triglycerides were higher while high-density lipoprotein cholesterol was lower in the WML-positive group than in the WML-negative group (P < 0.01 and P < 0.0001 respectively). Fasting plasma glucose (P < 0.0001), insulin concentrations (P < 0.0001), HOMA index (P < 0.0001) and HGF (< 0.0001) levels were higher in the WML-positive group than in the WML-negative group. Multivariate logistic analysis revealed that WML was independently predicted by the high HGF and insulin resistance (P < 0.0001 and P < 0.0001 respectively). CONCLUSION The results of this preliminary study indicate that the presence of WML was associated with the high HGF and insulin resistance in Japanese patients with type 2 diabetes mellitus.
Collapse
Affiliation(s)
- Futoshi Anan
- Department of Cardiology, Oita Red Cross Hospital, Oita, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
20
|
Rajpathak SN, Wang T, Wassertheil-Smoller S, Strickler HD, Kaplan RC, McGinn AP, Wildman RP, Rosenbaum D, Rohan TE, Scherer PE, Cushman M, Ho GYF. Hepatocyte growth factor and the risk of ischemic stroke developing among postmenopausal women: results from the Women's Health Initiative. Stroke 2010; 41:857-62. [PMID: 20203323 PMCID: PMC3903044 DOI: 10.1161/strokeaha.109.567719] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2009] [Accepted: 01/05/2010] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND PURPOSE Hepatocyte growth factor (HGF) is a potent angiogenic factor and may play a role in the development and progression of atherosclerotic lesions, the underlying mechanism of cardiovascular disease. However, there have been no prospective studies examining the relationship between HGF levels and risk of stroke. METHODS We conducted a nested case-control study (972 incident stroke cases and 1:1 age-matched and race-matched controls) to prospectively evaluate the association between plasma HGF and risk of ischemic stroke within the Women's Health Initiative Observational Study, a cohort of postmenopausal women aged 50 to 79 years. RESULTS Baseline HGF levels were correlated positively with body mass index, systolic blood pressure, low-density lipoprotein cholesterol, insulin resistance, and inflammatory markers, such as C-reactive protein, and inversely with high-density lipoprotein cholesterol (all P<0.05). Baseline HGF levels were higher among cases than controls (geometric means, 601.8 vs 523.2 pg/mL; P=0.003). Furthermore, the risk of incident ischemic stroke was significantly greater among women in the highest vs lowest quartile of plasma HGF levels (OR, 1.46; 95% CI, 1.12-1.91; P(trend)=0.003) in a conditional logistic regression model that adjusted for body mass index. These results were only slightly attenuated after further adjustment for additional stroke risk factors (OR, 1.39; 95% CI, 1.04-1.85; P(trend)=0.023). CONCLUSIONS Circulating levels of HGF are associated with an increased risk of incident ischemic stroke, independent of obesity and other risk factors for cardiovascular disease, among postmenopausal women aged 50 to 79 years.
Collapse
Affiliation(s)
- Swapnil N Rajpathak
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Yamamoto Y, Matsuura T, Narazaki G, Sugitani M, Tanaka K, Maeda A, Shiota G, Sato K, Yoshida A, Hisatome I. Synergistic effects of autologous cell and hepatocyte growth factor gene therapy for neovascularization in a murine model of hindlimb ischemia. Am J Physiol Heart Circ Physiol 2009; 297:H1329-36. [DOI: 10.1152/ajpheart.00321.2009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Autologous cell implantation and angiogenic gene therapy have been evaluated in critical limb ischemic patients. Here, we compared the features of these strategies individually and in combination. C57BL/6J mice with ischemic hindlimbs were injected with adherent mononuclear cells (aMNCs) from bone marrow or adenovirus encoding the hepatocyte growth factor (HGF) gene (Ad-HGF). Under comparable angiogenic conditions, 10 × 105 aMNCs produced significantly higher amounts of VEGF and FGF-2 and stimulated the number of arterioles in ischemic muscle compared with 1 × 108 plaque-forming units (pfu) of Ad-HGF. Ad-HGF produced 10 times more HGF in ischemic muscle compared with aMNCs. Injection of 0.3 × 105 aMNCs previously transfected with Ad-HGF (aMNC/Ad-HGF) increased blood flow and elevated the numbers of capillaries and arterioles to levels comparable with that seen with 10 × 105 aMNCs or 1 × 108 pfu of Ad-HGF. Hypoxic conditions induced the apoptotic death of aMNCs. However, coincubation with HGF or aMNC/Ad-HGF protected cells against apoptosis. HGF stimulated the migration of aMNCs, and the migration capacity of the aMNC/Ad-HGF group was significantly higher than that in the aMNC/Ad-LacZ group. In conclusion, cell-based HGF gene therapy decreased the number of cells required for neovascularization. This strategy can be an effective angiogenic therapy.
Collapse
Affiliation(s)
- Yasutaka Yamamoto
- Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences,
| | - Takashi Matsuura
- Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences,
| | - Genta Narazaki
- Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences,
| | - Miyoko Sugitani
- Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences,
| | - Kohei Tanaka
- Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences,
| | - Akihiro Maeda
- Division of Molecular Biology, Department of Molecular and Cellular Biology, School of Life Sciences, Faculty of Medicine, and
| | - Goshi Shiota
- Division of Molecular and Genetic Medicine, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Tottori, Japan
| | - Kenzo Sato
- Division of Molecular Biology, Department of Molecular and Cellular Biology, School of Life Sciences, Faculty of Medicine, and
| | - Akio Yoshida
- Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences,
| | - Ichiro Hisatome
- Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences,
| |
Collapse
|
|
22
|
Chu SH, Feng DF, Ma YB, Zhu ZA, Zhang H, Qiu JH. Stabilization of hepatocyte growth factor mRNA by hypoxia-inducible factor 1. Mol Biol Rep 2009; 36:1967-1975. [PMID: 18979225 DOI: 10.1007/s11033-008-9406-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2008] [Accepted: 10/21/2008] [Indexed: 01/23/2023]
Abstract
Hypoxia regulates expression of hepatocyte growth factor (HGF) by increasing its transcription and by stabilizing its mRNA. Despite the pivotal role of hypoxia-inducible factor 1 (HIF-1) in transcriptional activation of hypoxia-responsive genes, it is not known whether HIF-1 mediates hypoxia-induced stabilization of HGF mRNA. We constructed adenoviral vectors expressing either the wild-type HIF-1alpha (Ad2/HIF-1alpha/FL), a constitutively stable hybrid form of HIF-1alpha (Ad2/HIF-1alpha/VP16), or no transgene (Ad2/CMVEV). In rat glioma (C6) cells, human glioma (U251) cells human cardiac, vascular smooth muscle, and endothelial cells, infection with Ad2/HIF-1alpha/VP16 or Ad2/HIF-1alpha/FL increased HGF expression at both the mRNA and protein levels. Under normoxic conditions, the half-life of HGF mRNA was 43 min in C6 and U251 cells. Hypoxia and Ad2/HIF-1alpha/VP16 increased the half-life of HGF mRNA to 3.2 and 2.8 h, respectively, while Ad2/CMVEV had no effect. These studies are the first to demonstrate that overexpression of HIF-1alpha increases HGF mRNA stability. Our results also suggest that stabilization of HGF mRNA by hypoxia is mediated, at least in part, by HIF-1.
Collapse
Affiliation(s)
- Sheng-Hua Chu
- Department of Neurosurgery, No. 3 People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | | | | | | | | | | |
Collapse
|
|
23
|
Chanda D, Li T, Song KH, Kim YH, Sim J, Lee CH, Chiang JYL, Choi HS. Hepatocyte growth factor family negatively regulates hepatic gluconeogenesis via induction of orphan nuclear receptor small heterodimer partner in primary hepatocytes. J Biol Chem 2009; 284:28510-21. [PMID: 19720831 DOI: 10.1074/jbc.m109.022244] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Hepatic gluconeogenesis is tightly balanced by opposing stimulatory (glucagon) and inhibitory (insulin) signaling pathways. Hepatocyte growth factor (HGF) is a pleiotropic growth factor that mediates diverse biological processes. In this study, we investigated the effect of HGF and its family member, macrophage-stimulating factor (MSP), on hepatic gluconeogenesis in primary hepatocytes. HGF and MSP significantly repressed expression of the key hepatic gluconeogenic enzyme genes, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (Glc-6-Pase) and reduced glucose production. HGF and MSP activated small heterodimer partner (SHP) gene promoter and induced SHP mRNA and protein levels, and the effect of HGF and MSP on SHP gene expression was demonstrated to be mediated via activation of the AMP-activated protein kinase (AMPK) signaling pathway. We demonstrated that upstream stimulatory factor-1 (USF-1) specifically mediated HGF effect on SHP gene expression, and inhibition of USF-1 by dominant negative USF-1 significantly abrogated HGF-mediated activation of the SHP promoter. Elucidation of the mechanism showed that USF-1 bound to E-box-1 in the SHP promoter, and HGF increased USF-1 DNA binding on the SHP promoter via AMPK and DNA-dependent protein kinase-mediated pathways. Adenoviral overexpression of USF-1 significantly repressed PEPCK and Glc-6-Pase gene expression and reduced glucose production. Knockdown of endogenous SHP expression significantly reversed this effect. Finally, knockdown of SHP or inhibition of AMPK signaling reversed the ability of HGF to suppress hepatocyte nuclear factor 4alpha-mediated up-regulation of PEPCK and Glc-6-Pase gene expression along with the HGF- and MSP-mediated suppression of gluconeogenesis. Overall, our results suggest a novel signaling pathway through HGF/AMPK/USF-1/SHP to inhibit hepatic gluconeogenesis.
Collapse
Affiliation(s)
- Dipanjan Chanda
- Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Anan F, Masaki T, Yonemochi H, Takahashi N, Nakagawa M, Eshima N, Saikawa T, Yoshimatsu H. Hepatocyte growth factor levels are associated with the results of 123I-metaiodobenzylguanidine myocardial scintigraphy in patients with type 2 diabetes mellitus. Metabolism 2009; 58:167-73. [PMID: 19154948 DOI: 10.1016/j.metabol.2008.09.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2008] [Accepted: 09/11/2008] [Indexed: 11/24/2022]
Abstract
Elevated hepatocyte growth factor (HGF) levels and cardiovascular autonomic dysfunction are associated with a high mortality rate in patients with type 2 diabetes mellitus. We tested the hypothesis that elevated HGF is associated with insulin resistance and cardiovascular autonomic dysfunction in patients with type 2 diabetes mellitus not receiving insulin treatment. The study group consisted of 21 type 2 diabetes mellitus patients with high HGF levels (>0.26 ng/mL, 58 +/- 5 years old, high-HGF group). The control group consisted of 25 type 2 diabetes mellitus patients with normal HGF levels (<or=0.26 ng/mL, 58 +/- 9 years old, normal-HGF group). Cardiovascular autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations, and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphy. Early and delayed (123)I-MIBG myocardial uptake values were lower (P < .005 and P < .01, respectively) and the percentage of washout rate of (123)I-MIBG was higher (P < .001) in the high-HGF group than in the normal-HGF group. The fasting plasma insulin concentrations (P < .0001) and the homeostasis model assessment index values (P < .0001) were higher in the high-HGF group than in the normal-HGF group. Multiple regression analysis revealed that the level of HGF was independently predicted by the homeostasis model assessment index values and the myocardial uptake of (123)I-MIBG at the delayed phase. Our results demonstrate that high levels of HGF are associated with depressed cardiovascular autonomic function and insulin resistance in patients with type 2 diabetes mellitus.
Collapse
Affiliation(s)
- Futoshi Anan
- Department of Cardiology, Oita Red Cross Hospital, Oita 870-0033, Japan.
| | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Bibliography. Current world literature. Diabetes and the endocrine pancreas II. Curr Opin Endocrinol Diabetes Obes 2007; 14:329-57. [PMID: 17940461 DOI: 10.1097/med.0b013e3282c3a898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
26
|
Anan F, Shimomura T, Imagawa M, Masaki T, Nawata T, Takahashi N, Yonemochi H, Eshima N, Saikawa T, Yoshimatsu H. Predictors for silent cerebral infarction in patients with chronic renal failure undergoing hemodialysis. Metabolism 2007; 56:593-8. [PMID: 17445532 DOI: 10.1016/j.metabol.2007.01.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2006] [Accepted: 12/23/2006] [Indexed: 11/18/2022]
Abstract
In patients with chronic renal failure undergoing hemodialysis (HD), silent cerebral infarctions (SCIs) are associated with high mortality. Levels of hepatocyte growth factor (HGF) increase with renal dysfunction and may be a novel predictor of cerebrovascular events. We examined if HGF is a predictor of SCI in HD patients. Brain magnetic resonance imaging findings were used to divide 50 patients undergoing HD into 2 groups, a group with SCI (age, 61 +/- 8 years, mean +/- SD; n = 27) and a group without SCI (age, 60 +/- 7 years; n = 23). These patients received 24-hour ambulatory blood pressure monitoring. The number of patients with diabetes or hypertension was not different between the 2 groups. We made the following observations: (1) The percentage of smokers was higher in the group with SCI than in the group without SCI (P < .05). (2) Plasma levels of high-density lipoprotein cholesterol were lower and HGF levels were higher in the group with SCI compared with the group without SCI (P < .05 and P < .005, respectively). (3) Systolic ambulatory blood pressure and mean heart rate at night were higher in the group with SCI than in the group without SCI (P < .05). Multiple logistic regression analysis identified HGF as a significant risk factor for SCI (odds ratio, 1.89; 95% confidence interval, 1.57-3.38; P < .005). Our findings indicate that HGF may be a novel useful predictor of SCI in patients with chronic renal failure undergoing HD.
Collapse
Affiliation(s)
- Futoshi Anan
- Department of Cardiology, Oita Red Cross Hospital, Oita, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Bibliography. Current world literature. Diabetes and the endocrine pancreas. Curr Opin Endocrinol Diabetes Obes 2007; 14:170-96. [PMID: 17940437 DOI: 10.1097/med.0b013e3280d5f7e9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|