|
1
|
Gunn NA, Oo Y, Lee CWL, Heaney E, Tan NYT, Chan YZ, Wang SSY. Disseminated Intravascular Coagulopathy and Persistent Inflammation, Immunosuppression, and Catabolism Syndrome: Pathophysiology, shared pathways, and clinical implications. Thromb Res 2025; 250:109321. [PMID: 40286453 DOI: 10.1016/j.thromres.2025.109321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/31/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Disseminated Intravascular Coagulopathy (DIC) and Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) are critical care syndromes that frequently coexist in critically ill patients, but mechanisms underlying their shared pathways are not well understood. OBJECTIVE This review discusses the pathophysiology of DIC and PICS and explores the shared mechanisms behind DIC and PICS and their implications for clinical management. FINDINGS DIC and PICS share a common pathophysiological foundation of endothelial dysfunction, coagulation dysregulation, and inflammation, leading to a vicious cycle of microvascular injury and systemic inflammation, culminating in organ dysfunction. DIC has also been identified as an independent risk factor for PICS. Anticoagulation therapies such as antithrombin, recombinant human soluble thrombomodulin (rhTM), and heparin attenuates inflammation, a mechanism underlying both syndromes, thereby improving outcomes in PICS. CONCLUSION DIC and PICS share critical pathophysiological pathways that exacerbate outcomes in critically ill patients. Recognizing these interconnections is essential for developing targeted therapies. Standardizing PICS definitions and advancing research to clarify mechanisms, interplay, and causality between DIC and PICS are crucial next steps.
Collapse
Affiliation(s)
- Nicole Ann Gunn
- University of Queensland School of Medicine, Herston, QLD 4006, Australia
| | - Yukei Oo
- University of Queensland School of Medicine, Herston, QLD 4006, Australia
| | | | - Edward Heaney
- University of Queensland School of Medicine, Herston, QLD 4006, Australia
| | | | - Yan Zhi Chan
- Duke-NUS Medical School, Singapore 169857, Singapore
| | - Samuel Sherng Young Wang
- Duke-NUS Medical School, Singapore 169857, Singapore; Department of Internal Medicine, Singapore General Hospital, Singapore 169608, Singapore.
| |
Collapse
|
|
2
|
Liu C, Li S, Wang Z, Li Z, Fang Z, Zhang Y, Gao Y. Safety profile of faricimab: a multi-source pharmacovigilance analysis using FAERS and JADER. BMC Pharmacol Toxicol 2025; 26:82. [PMID: 40221797 PMCID: PMC11994024 DOI: 10.1186/s40360-025-00902-6] [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: 12/20/2024] [Accepted: 03/11/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Faricimab is a bispecific antibody targeting vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), offering a novel therapeutic approach for ocular diseases. However, its long-term safety profile remains under evaluation. This study analyzes its adverse events (AEs) using the U.S. FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER). METHODS AEs from FAERS (2004-2024) and JADER (2004-2024) were analyzed using disproportionality algorithms. Subgroup analyses assessed differences by age and sex. AE onset time was also assessed. RESULTS Several newly identified adverse events (AEs) were observed, including macular ischemia, keratic precipitates, and optic nerve injury, with strong safety signals detected in both FAERS and JADER. For instance, macular ischemia showed a high association with faricimab use (ROR = 260.46), suggesting a potential risk of retinal circulation impairment. Similarly, keratic precipitates (ROR = 739.65) indicate a notable inflammatory response. All these findings highlight the need for closer monitoring of ocular complications, particularly in high-risk patient groups. The FAERS database mainly reported retinal occlusive vasculitis, ocular vasculitis, and keratic precipitates, while JADER predominantly featured retinal occlusive vasculitis and retinal vascular occlusion. Sex-based differences indicated a higher risk of inflammatory AEs in females (e.g., uveitis and eye inflammation) and a greater incidence of retinal vascular events in males (e.g., retinal vasculitis). Age-related differences showed that older patients (≥65 years) had lower inflammatory AE risks but were more prone to optic nerve damage and retinal atrophy, while younger patients (<65 years) exhibited a higher risk of vitreous hemorrhage and cataracts. CONCLUSIONS This study identified previously unreported safety signals, suggesting the need for potential updates to faricimab's safety labeling. Faricimab's dual-target mechanism presents unique safety concerns. Clinicians should monitor ocular inflammation and vascular complications, particularly in younger males and Asian patients. Further studies using real-world data are needed to validate these findings.
Collapse
Affiliation(s)
- Chuanya Liu
- Department of Ophthalmology, The First Affiliated Hospital (Shanghai Changhai Hospital), Naval Medical University, Shanghai, China
| | - Shangze Li
- Department of Orthopedics, Changzhou Medical District, No. 904 Hospital of PLA Joint Logistic Support Force, Changzhou, China
| | - Ziyi Wang
- Department of Ophthalmology, The First Affiliated Hospital (Shanghai Changhai Hospital), Naval Medical University, Shanghai, China
| | - Zhifu Li
- Department of Ophthalmology, The First Affiliated Hospital (Shanghai Changhai Hospital), Naval Medical University, Shanghai, China
| | - Zhou Fang
- Department of Ophthalmology, The First Affiliated Hospital (Shanghai Changhai Hospital), Naval Medical University, Shanghai, China
| | - Yuan Zhang
- Department of Ophthalmology, The First Affiliated Hospital (Shanghai Changhai Hospital), Naval Medical University, Shanghai, China.
| | - Yu Gao
- Department of Ophthalmology, The First Affiliated Hospital (Shanghai Changhai Hospital), Naval Medical University, Shanghai, China.
| |
Collapse
|
|
3
|
Andrés-Blasco I, Gallego-Martínez A, Casaroli-Marano RP, Di Lauro S, Arévalo JF, Pinazo-Durán MD. Molecular-Genetic Biomarkers of Diabetic Macular Edema. J Clin Med 2024; 13:7426. [PMID: 39685883 DOI: 10.3390/jcm13237426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/23/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
Background: Diabetic macular edema (DME) is a leading cause of vision impairment and blindness among diabetic patients, requiring effective diagnostic and monitoring strategies. This systematic review aims to synthesize current knowledge on molecular biomarkers associated with DME, focusing on their potential to improve diagnostic accuracy and disease management. Methods: A comprehensive search was conducted in PubMed, Embase, Medline, and the Cochrane Central Register of Controlled Trials, covering literature from 2004 to 2023. Out of 1074 articles initially identified, 48 relevant articles were included in this systematic review. Results: We found that molecules involved in several cellular processes, such as neuroinflammation, oxidative stress, vascular dysfunction, apoptosis, and cell-to-cell communication, exhibit differential expression profiles in various biological fluids when comparing diabetic individuals with or without macular edema. Conclusions: The study of these molecules could lead to the proper identification of specific biomarkers that may improve the diagnosis, prognosis, and therapeutic management of DME patients.
Collapse
Affiliation(s)
- Irene Andrés-Blasco
- Ophthalmic Research Unit "Santiago Grisolía"/Fisabio, 46017 Valencia, Spain
- Cellular and Molecular Ophthalmo-Biology Group, Department of Surgery, Faculty of Medicina and Odontology, University of Valencia, 46017 Valencia, Spain
- Research Network in Inflammatory Diseases and Immunopathology of Organs and Systems "REI-RICORS", RD21/0002/0032, Institute of Health Carlos III, 28029 Madrid, Spain
| | - Alex Gallego-Martínez
- Ophthalmic Research Unit "Santiago Grisolía"/Fisabio, 46017 Valencia, Spain
- Cellular and Molecular Ophthalmo-Biology Group, Department of Surgery, Faculty of Medicina and Odontology, University of Valencia, 46017 Valencia, Spain
| | - Ricardo Pedro Casaroli-Marano
- Research Network in Inflammatory Diseases and Immunopathology of Organs and Systems "REI-RICORS", RD21/0002/0032, Institute of Health Carlos III, 28029 Madrid, Spain
- Department of Surgery, School of Medicine and Hospital Clínic de Barcelona, Universitat de Barcelona, 08036 Barcelona, Spain
| | - Salvatore Di Lauro
- Department of Ophthalmology, University Clinic Hopital, 47003 Valladolid, Spain
| | - Jose Fernando Arévalo
- Research Network in Inflammatory Diseases and Immunopathology of Organs and Systems "REI-RICORS", RD21/0002/0032, Institute of Health Carlos III, 28029 Madrid, Spain
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Maria Dolores Pinazo-Durán
- Ophthalmic Research Unit "Santiago Grisolía"/Fisabio, 46017 Valencia, Spain
- Cellular and Molecular Ophthalmo-Biology Group, Department of Surgery, Faculty of Medicina and Odontology, University of Valencia, 46017 Valencia, Spain
- Research Network in Inflammatory Diseases and Immunopathology of Organs and Systems "REI-RICORS", RD21/0002/0032, Institute of Health Carlos III, 28029 Madrid, Spain
| |
Collapse
|
|
4
|
Warmke N, Bridge KI, Ozber CH, Smith J, Platt F, Haywood NJ, Skromna A, Makava N, Yuldasheva NY, Wheatcroft S, Kearney MT, Cubbon RM, Griffin KJ. Insulin receptor signalling in PDGFRβ-expressing cells influences systemic metabolism and negatively impacts lipid storage. Biochem Biophys Res Commun 2024; 735:150799. [PMID: 39406023 DOI: 10.1016/j.bbrc.2024.150799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 09/19/2024] [Accepted: 10/07/2024] [Indexed: 11/05/2024]
Abstract
Pericytes are vascular mural cells that support the microvasculature; their dysfunction contributes to diabetic retinopathy and has been linked to obesity in humans. To explore the role of pericyte insulin signalling on systemic metabolism we utilised male mice from our previously described PIR-/- (PIRKO) mouse line which has insulin receptor (Insr) knockout in PDGFRβ-expressing cells. These animals exhibit systemic insulin resistance from as early as 8-weeks of age, despite no change in body weight or activity level, and show altered body composition and hepatosteatosis. When challenged with high fat diet, PIR-/- remain insulin resistant but are protected from weight gain with reduced adipose tissue expansion across all depots and altered adipose morphology. Exhibiting parallels with the metabolically-obese-normal-weight (MONW) human phenotype, the PIR-/- line underlines the importance of pericyte biology in the development of both diabetes and obesity and establishes the angiopoietin (Ang)/Tie signalling pathway as a focus for future research.
Collapse
Affiliation(s)
- Nele Warmke
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK
| | - Katherine I Bridge
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK
| | - Claire H Ozber
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK; Leeds Institute of Medical Research at St James' Hospital, Faculty of Medicine and Health, University of Leeds, Beckett Street, LS9 7TF, UK
| | - Jessica Smith
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK
| | - Fiona Platt
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK
| | - Natalie J Haywood
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK
| | - Anna Skromna
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK
| | - Natallia Makava
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK
| | - Nadira Y Yuldasheva
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK
| | - Stephen Wheatcroft
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK
| | - Mark T Kearney
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK
| | - Richard M Cubbon
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK
| | - Kathryn J Griffin
- Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK.
| |
Collapse
|
|
5
|
Salem NAB, Ismail WM, Hendawy SR, Abdelrahman AM, El-Refaey AM. Serum angiopoietin-2: a promising biomarker for early diabetic kidney disease in children and adolescents with type 1 diabetes. Eur J Pediatr 2024; 183:3853-3862. [PMID: 38884820 PMCID: PMC11322226 DOI: 10.1007/s00431-024-05637-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/20/2024] [Accepted: 05/30/2024] [Indexed: 06/18/2024]
Abstract
Albuminuria has been considered the golden standard biomarker for diabetic kidney disease (DKD), but appears once significant kidney damage has already occurred. Angiopoietin-2 (Angpt-2) has been implicated in the development and progression of DKD in adults. We aimed to explore the association of serum Angpt-2 levels with DKD in children and adolescents with type 1 diabetes mellitus (T1DM) of short duration (3-5 years) and to evaluate the predictive power of serum Angpt-2 in the early detection of DKD prior to the microalbuminuric phase. The current cross-sectional study included 90 children divided into three age and sex-matched groups based on urinary albumin-to-creatinine ratio (UACR): microalbuminuric diabetic group (n = 30), non-albuminuric diabetic group (n = 30), and control group (n = 30). All participants were subjected to anthropometric measurements, serum Angpt-2 and fasting lipid profile (total cholesterol, triglycerides, LDL-C, HDL-C, and Non-HDL-C) assessment. Glomerular filtration rate was estimated based on serum creatinine (eGFR-Cr). Higher serum Angpt-2 levels were detected in both diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric diabetic group. There was no detected significant difference in eGFR-Cr values across the study groups. Serum Angpt-2 was positively correlated with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR, while UACR, HbA1c, and Non-HDL-C were independent predictors for serum Angpt-2. Serum Angpt-2 at level of 137.4 ng/L could discriminate between microalbuminuric and non-albuminuric diabetic groups with AUC = 0.960 and at level of 115.95 ng/L could discriminate between the non-albuminuric diabetic group and controls with AUC = 0.976.Conclusion: Serum Angpt-2 is a promising potent biomarker for the detection of early stage of DKD in childhood T1DM before albuminuria emerges. What is Known? • Urine albumin-to-creatinine ratio (UACR) and glomerular filtration rate (GFR) are the golden standard but late biomarkers for DKD. • Angiopoietin-2 has been implicated in the development and progression of DKD in adults with diabetes, but has not been explored in T1DM children with DKD. What is New? • Higher serum angiopoietin-2 was detected in diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric group. • Angiopoietin-2 correlated positively with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR. • Serum angiopoietin-2 is a promising early diagnostic biomarker for DKD in children with T1DM.
Collapse
Affiliation(s)
- Nanees Abdel-Badie Salem
- Pediatric Endocrinology and Diabetes Unit, Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Wafaa M Ismail
- Mansoura University Children's Hospital, Mansoura, Egypt
| | - Shimaa R Hendawy
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ashraf M Abdelrahman
- Department of Diagnostic Radiology, Mansoura University Children's Hospital, Mansoura, Egypt
| | - Ahmed M El-Refaey
- Nephrology Unit, Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| |
Collapse
|
|
6
|
Alshawaf E, Abu-Farha M, Mohammad A, Devarajan S, Al-Khairi I, Cherian P, Ali H, Al-Matrouk H, Al-Mulla F, Al Attar A, Abubaker J. Angiopoietin-2 and Angiopoietin-like Proteins with a Prospective Role in Predicting Diabetic Nephropathy. Biomedicines 2024; 12:949. [PMID: 38790911 PMCID: PMC11118931 DOI: 10.3390/biomedicines12050949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 04/14/2024] [Accepted: 04/20/2024] [Indexed: 05/26/2024] Open
Abstract
Angiopoietins are crucial growth factors for maintaining a healthy, functional endothelium. Patients with type 2 diabetes (T2D) exhibit significant levels of angiogenic markers, particularly Angiopoietin-2, which compromises endothelial integrity and is connected to symptoms of endothelial injury and failure. This report examines the levels of circulating angiopoietins in people with T2D and diabetic nephropathy (DN) and explores its link with ANGPTL proteins. We quantified circulating ANGPTL3, ANGPTL4, ANGPTL8, Ang1, and Ang2 in the fasting plasma of 117 Kuwaiti participants, of which 50 had T2D and 67 participants had DN. The Ang2 levels increased with DN (4.34 ± 0.32 ng/mL) compared with T2D (3.42 ± 0.29 ng/mL). This increase correlated with clinical parameters including the albumin-to-creatinine ratio (ACR) (r = 0.244, p = 0.047), eGFR (r = -0.282, p = 0.021), and SBP (r = -0.28, p = 0.024). Furthermore, Ang2 correlated positively to both ANGPTL4 (r = 0.541, p < 0.001) and ANGPTL8 (r = 0.41, p = 0.001). Multiple regression analysis presented elevated ANGPTL8 and ACRs as predictors for Ang2's increase in people with DN. In people with T2D, ANGPTL4 positively predicted an Ang2 increase. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis of the combination of Ang2 and ANGPTL8 was 0.77 with 80.7% specificity. In conclusion, significantly elevated Ang2 in people with DN correlated with clinical markers such as the ACR, eGFR, and SBP, ANGPTL4, and ANGPTL8 levels. Collectively, this study highlights a close association between Ang2 and ANGPTL8 in a population with DN, suggesting them as DN risk predictors.
Collapse
Affiliation(s)
- Eman Alshawaf
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (E.A.); (M.A.-F.); (A.M.); (I.A.-K.); (P.C.)
| | - Mohamed Abu-Farha
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (E.A.); (M.A.-F.); (A.M.); (I.A.-K.); (P.C.)
- Diabetology Unit, Amiri Hospital, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Anwar Mohammad
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (E.A.); (M.A.-F.); (A.M.); (I.A.-K.); (P.C.)
| | - Sriraman Devarajan
- National Dasman Diabetes Biobank, Dasman Diabetes Institute, Dasman 15462, Kuwait;
| | - Irina Al-Khairi
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (E.A.); (M.A.-F.); (A.M.); (I.A.-K.); (P.C.)
| | - Preethi Cherian
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (E.A.); (M.A.-F.); (A.M.); (I.A.-K.); (P.C.)
| | - Hamad Ali
- Functional Genomic Unit, Dasman Diabetes Institute, Dasman 15462, Kuwait; (H.A.); (F.A.-M.)
- Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Health Sciences Center, Kuwait University, Kuwait 15462, Kuwait
| | - Hawra Al-Matrouk
- Medical Department, Amiri Hospital, Ministry of Health, Kuwait 15462, Kuwait;
| | - Fahd Al-Mulla
- Functional Genomic Unit, Dasman Diabetes Institute, Dasman 15462, Kuwait; (H.A.); (F.A.-M.)
- Department of Translational Research, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Abdulnabi Al Attar
- Diabetology Unit, Amiri Hospital, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Jehad Abubaker
- National Dasman Diabetes Biobank, Dasman Diabetes Institute, Dasman 15462, Kuwait;
| |
Collapse
|
|
7
|
Mohebi R, Liu Y, Hansen MK, Yavin Y, Sattar N, Pollock CA, Butler J, Jardine M, Masson S, Heerspink HJ, Januzzi JL. Associations of Angiopoietin 2 and Vascular Endothelial Growth Factor-A Concentrations with Clinical End Points. Clin J Am Soc Nephrol 2024; 19:429-437. [PMID: 38099944 PMCID: PMC11020427 DOI: 10.2215/cjn.0000000000000389] [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: 08/28/2023] [Accepted: 12/11/2023] [Indexed: 01/09/2024]
Abstract
BACKGROUND Angiopoietin 2 regulates endothelial function partially mediated by vascular endothelial growth factor-A (VEGF-A) and may play a role in diabetic kidney disease (DKD). We assessed the association of angiopoietin 2 and VEGF-A with cardiorenal outcomes and investigated the effect of canagliflozin on angiopoietin 2 and VEGF-A concentrations. METHODS Two thousand five hundred sixty-five study participants with DKD and available plasma samples treated with canagliflozin or placebo in the Canagliflozin and Kidney Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial were included. Angiopoietin 2 and VEGF-A concentrations were measured at baseline, year 1, and year 3. The primary composite end point of the trial was a composite of kidney failure, doubling of the serum creatinine level, and kidney or cardiovascular death. RESULTS Patients with the highest baseline quartile of angiopoietin 2, but not VEGF-A, concentration had the highest risk clinical profile. Treatment with canagliflozin significantly lowered concentrations of angiopoietin 2 (adjusted geometric mean ratio: 0.94; 95% confidence interval, 0.92 to 0.95; P < 0.001), but not VEGF-A. In multivariable-adjusted modeling, each 50% increment in log baseline angiopoietin 2 concentrations was associated with a higher risk of primary composite outcome (hazard ratio, 1.27; 95% confidence interval, 1.13 to 1.43). Angiopoietin 2 change at year 1 compared with baseline explained 10% of the effect of canagliflozin on the primary composite outcome. VEGF-A concentrations were not associated with outcomes, alone or in combination with angiopoietin 2. CONCLUSIONS Higher angiopoietin 2 levels were associated with cardiorenal risk among individuals with DKD independent of VEGF-A. Canagliflozin lowered angiopoietin 2 concentrations. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy, NCT02065791 .
Collapse
Affiliation(s)
- Reza Mohebi
- Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Yuxi Liu
- Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | | | - Yshai Yavin
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Naveed Sattar
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Carol A. Pollock
- Kolling Institute, Royal North Shore Hospital University of Sydney, Sydney, New South Wales, Australia
| | - Javed Butler
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
- Baylor Scott & White Institute, Dallas, Texas
| | - Meg Jardine
- The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia
- Concord Repatriation General Hospital, Sydney, New South Wales, Australia
| | - Serge Masson
- Roche Diagnostics International, Rotkreuz, Switzerland
| | - Hiddo J.L. Heerspink
- Department Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands
| | - James L. Januzzi
- Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Heart Failure and Biomarker Trials, Baim Institute for Clinical Research, Boston, Massachusetts
| |
Collapse
|
|
8
|
Yildiz AB, Copur S, Tanriover C, Yavuz F, Vehbi S, Gaipov A, Magagnoli L, Ciceri P, Cozzolino M, Kanbay M. Angiopoietin as a Novel Prognostic Marker in Kidney Disease. Blood Purif 2024; 53:425-435. [PMID: 38262381 DOI: 10.1159/000536439] [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: 07/18/2023] [Accepted: 11/12/2023] [Indexed: 01/25/2024]
Abstract
INTRODUCTION Renal injury is among the leading causes of morbidity and mortality; however, there are no reliable indicators for determining the likelihood of developing chronic kidney disease (CKD), CKD progression, or AKI events. Vascular growth factors called angiopoietins have a role in endothelial function, vascular remodeling, tissue stabilization, and inflammation and have been implicated as prognostic and predictive markers in AKI. METHODS Although the exact mechanism of the relationship between kidney injury and angiopoietins is unknown, this review demonstrates that AKI patients have higher angiopoietin-2 levels and that higher angiopoietin-1 to angiopoietin-2 ratio may potentially be linked with a reduced risk of the CKD progression. RESULTS This review therefore emphasizes the importance of angiopoietin-2 and proposes that it could be an important predictor of AKI in clinical settings. CONCLUSION There is a need for further large-scale randomized clinical trials in order to have a better understanding of the significance of angiopoietin-2 and for the determination of its potential clinical implications.
Collapse
Affiliation(s)
- Abdullah B Yildiz
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Cem Tanriover
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Furkan Yavuz
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sezan Vehbi
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Abduzhappar Gaipov
- Department of Medicine, Nazarbayev Unive Mario Cozzolino Rsity School of Medicine, Astana, Kazakhstan
- Clinical Academic Department of Internal Medicine, CF "University Medical Center", Astana, Kazakhstan
| | - Lorenza Magagnoli
- Department of Health Sciences, Renal Division, University of Milan, Milan, Italy
| | - Paola Ciceri
- Department of Health Sciences, Renal Division, University of Milan, Milan, Italy
| | - Mario Cozzolino
- Department of Health Sciences, Renal Division, University of Milan, Milan, Italy
| | - Mehmet Kanbay
- Department of Medicine, Nephrology, Koc University School of Medicine, Istanbul, Turkey
| |
Collapse
|
|
9
|
Agyekum JA, Yeboah K. Angiopoietin-2 Is Associated with Aortic Stiffness in Diabetes Patients in Ghana: A Case-Control Study. Int J Vasc Med 2023; 2023:3155982. [PMID: 37869582 PMCID: PMC10586911 DOI: 10.1155/2023/3155982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 09/28/2023] [Accepted: 09/29/2023] [Indexed: 10/24/2023] Open
Abstract
Objective Impaired angiogenesis, measured as serum levels of angiogenic growth factors, may be among the mechanisms underlining aortic stiffness in diabetes patients. We studied the association between aortic stiffness and circulating angiogenic growth factors in type 2 diabetes (T2DM) patients without any organ damage. Methods In a case-control design, aortic pulse wave velocity (PWV), augmentation index (AIx), and aortic blood pressures (BPs) were measured in 140 T2DM patients and 110 nondiabetic controls. Fasting blood samples were collected to measure the levels of angiopoietin- (Ang-) 1, Ang-2, and vascular endothelial growth factor-A (VEGF). Results Compared to nondiabetes participants, T2DM patients had increased PWV (8.7 ± 1.5 vs. 7.6 ± 1.3, p = 0.031), aortic pulse BP (58 ± 20 vs. 49 ± 17, p = 0.011), Ang-2 (838 (473-1241) vs. 597 (274-1005), p = 0.018), and VEGF (72.2 (28-201.8) vs. 48.4 (17.4-110.1), p = 0.025) but reduced levels of AIx (21.7 ± 13.8 vs. 34 ± 12.9, p < 0.001) and Ang-1 (33.1 (24.7-42.1) vs. 41.1 (30-57.3), p = 0.01). In all study participants, compared to those in the lower tertile, participants in the upper tertile of Ang-2 had increased odds of PWV (2.01 (1.17-3.84), p = 0.004), aortic systolic BP (1.24 (1.04-1.97), p = 0.011), and aortic pulse BP (1.19 (1.04-1.82), p = 0.041) but reduced odds of AIx (0.84 (0.71-0.96), p = 0.014) in multivariable-adjusted models. Conclusion In our study population, increased circulating Ang-2 was associated with increased levels of aortic stiffness parameters.
Collapse
Affiliation(s)
- Jennifer A. Agyekum
- Department of Physiology, University of Ghana Medical School, Accra, Ghana
- Medical Laboratory Unit, Mamprobi Hospital, Ghana Health Service, Accra, Ghana
| | - Kwame Yeboah
- Department of Physiology, University of Ghana Medical School, Accra, Ghana
| |
Collapse
|
|
10
|
Collazos-Alemán JD, Gnecco-González S, Jaramillo-Zarama B, Jiménez-Mora MA, Mendivil CO. The Role of Angiopoietins in Neovascular Diabetes-Related Retinal Diseases. Diabetes Ther 2022; 13:1811-1821. [PMID: 36331711 PMCID: PMC9663771 DOI: 10.1007/s13300-022-01326-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022] Open
Abstract
Diabetic retinopathy is a devastating and frequent complication of poorly controlled diabetes, whose pathogenesis is still only partially understood. Advances in basic research over the last two decades have led to the discovery of angiopoietins, proteins that strongly influence the growth and integrity of blood vessels in many vascular beds, with particular importance in the retina. Angiopoietin 1 (Ang1), produced mostly by pericytes and platelets, and angiopoietin 2 (Ang2), produced mainly by endothelial cells, bind to the same receptor (Tie2), but exert opposing effects on target cells. Ang1 maintains the stability of the mature vasculature, while Ang2 promotes vessel wall destabilization and disruption of the connections between endothelial cells and pericytes. Human retinal endothelial cells exposed to Ang2 show reduced membrane expression of the adhesion molecule VE-cadherin, and patients with proliferative diabetic retinopathy or diabetic macular edema have markedly increased vitreal concentrations of Ang2. Faricimab, a bi-specific antibody simultaneously directed against Ang2 and VEGF, has shown promising results in clinical trials among patients with diabetic retinopathy, and other agents targeting the angiopoietin system are currently in development.
Collapse
Affiliation(s)
| | - Sofía Gnecco-González
- School of Medicine, Universidad de los Andes, Carrera 7 No 116-05, Of 413, Bogotá, Colombia
| | | | - Mario A Jiménez-Mora
- Department of Ophthalmology, Faculty of Medicine, National University of Colombia, Bogotá, Colombia
| | - Carlos O Mendivil
- School of Medicine, Universidad de los Andes, Carrera 7 No 116-05, Of 413, Bogotá, Colombia.
- Section of Endocrinology, Fundación Santa Fe de Bogotá, Bogotá, Colombia.
| |
Collapse
|
|
11
|
Chang FC, Liu CH, Luo AJ, Tao-Min Huang T, Tsai MH, Chen YJ, Lai CF, Chiang CK, Lin TH, Chiang WC, Chen YM, Chu TS, Lin SL. Angiopoietin-2 inhibition attenuates kidney fibrosis by hindering chemokine C-C motif ligand 2 expression and apoptosis of endothelial cells. Kidney Int 2022; 102:780-797. [DOI: 10.1016/j.kint.2022.06.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 06/16/2022] [Accepted: 06/23/2022] [Indexed: 12/17/2022]
|
|
12
|
Increased frequency of proangiogenic tunica intima endothelial kinase 2 (Tie2) expressing monocytes in individuals with type 2 diabetes mellitus. Cardiovasc Diabetol 2022; 21:72. [PMID: 35549955 PMCID: PMC9102255 DOI: 10.1186/s12933-022-01497-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 02/18/2022] [Indexed: 12/02/2022] Open
Abstract
Background Individuals with type 2 diabetes mellitus (T2DM) have an increased risk for developing macrovascular disease (MVD) manifested by atherosclerosis. Phenotypically and functionally different monocyte subsets (classical; CD14++CD16−, non-classical; CD14+CD16++, and intermediate; CD14++CD16+) including pro-angiogenic monocytes expressing Tie2 (TEMs) can be identified. Here we investigated monocyte heterogeneity and its association with T2DM and MVD. Methods Individuals with (N = 51) and without (N = 56) T2DM were recruited and allocated to "non-MVD" or "with MVD" (i.e., peripheral or coronary artery disease) subgroups. Blood monocyte subsets were quantified based on CD14, CD16 and Tie2 expression levels. Plasma levels of Tie2-ligands angiopoietin-1 and angiopoietin-2 were determined using ELISA. Carotid endarterectomy samples from individuals with (N = 24) and without (N = 22) T2DM were stained for intraplaque CD68+ macrophages (inflammation) and CD34+ (angiogenesis), as plaque vulnerability markers. Results Monocyte counts were similar between individuals with T2DM and healthy controls (non-diabetic, non-MVD). Non-classical monocytes were reduced (p < 0.05) in T2DM, whereas the percentage of TEMs within the intermediate subset was increased (p < 0.05). T2DM was associated with increased angiopoietin-1 (p < 0.05) and angiopoietin-2 (p = 0.0001) levels. Angiopoietin-2 levels were higher in T2DM individuals with MVD compared with non-MVD (p < 0.01). Endarterectomized plaques showed no differences in macrophage influx and microvessel number between individuals with and without T2DM. Conclusions Monocyte subset distribution is altered in T2DM with reduced non-classical monocytes and increased TEM percentage in the intermediate monocyte subset. Increased angiopoietin-2 levels together with increased frequency of TEMs might promote plaque vulnerability in T2DM which could however not be confirmed at tissue level in advanced atherosclerotic lesions.
Collapse
|
|
13
|
Marei I, Chidiac O, Thomas B, Pasquier J, Dargham S, Robay A, Vakayil M, Jameesh M, Triggle C, Rafii A, Jayyousi A, Al Suwaidi J, Abi Khalil C. Angiogenic content of microparticles in patients with diabetes and coronary artery disease predicts networks of endothelial dysfunction. Cardiovasc Diabetol 2022; 21:17. [PMID: 35109843 PMCID: PMC8812242 DOI: 10.1186/s12933-022-01449-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/20/2022] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Elevated endothelial microparticles (EMPs) levels are surrogate markers of vascular dysfunction. We analyzed EMPs with apoptotic characteristics and assessed the angiogenic contents of microparticles in the blood of patients with type 2 diabetes (T2D) according to the presence of coronary artery disease (CAD). METHODS A total of 80 participants were recruited and equally classified as (1) healthy without T2D, (2) T2D without cardiovascular complications, (3) T2D and chronic coronary artery disease (CAD), and (4) T2D and acute coronary syndrome (ACS). MPs were isolated from the peripheral circulation, and EMPs were characterized using flow cytometry of CD42 and CD31. CD62E was used to determine EMPs' apoptotic/activation state. MPs content was extracted and profiled using an angiogenesis array. RESULTS Levels of CD42- CD31 + EMPs were significantly increased in T2D with ACS (257.5 ± 35.58) when compared to healthy subjects (105.7 ± 12.96, p < 0.01). There was no significant difference when comparing T2D with and without chronic CAD. The ratio of CD42-CD62 +/CD42-CD31 + EMPs was reduced in all T2D patients, with further reduction in ACS when compared to chronic CAD, reflecting a release by apoptotic endothelial cells. The angiogenic content of the full population of MPs was analyzed. It revealed a significant differential expression of 5 factors in patients with ACS and diabetes, including TGF-β1, PD-ECGF, platelet factor 4, serpin E1, and thrombospondin 1. Ingenuity Pathway Analysis revealed that those five differentially expressed molecules, mainly TGF-β1, inhibit key pathways involved in normal endothelial function. Further comparison of the three diabetes groups to healthy controls and diabetes without cardiovascular disease to diabetes with CAD identified networks that inhibit normal endothelial cell function. Interestingly, DDP-IV was the only differentially expressed protein between chronic CAD and ACS in patients with diabetes. CONCLUSION Our data showed that the release of apoptosis-induced EMPs is increased in diabetes, irrespective of CAD, ACS patients having the highest levels. The protein contents of MPs interact in networks that indicate vascular dysfunction.
Collapse
Affiliation(s)
- Isra Marei
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Doha, Qatar
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Omar Chidiac
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Binitha Thomas
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Jennifer Pasquier
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Soha Dargham
- Biostatistics Core, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Amal Robay
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Muneera Vakayil
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | | | | | - Arash Rafii
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Amin Jayyousi
- Department of Endocrinology, Hamad Medical Corporation, Doha, Qatar
| | | | - Charbel Abi Khalil
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar.
- Heart Hospital, Hamad Medical Corporation, Doha, Qatar.
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, USA.
| |
Collapse
|
|
14
|
Thakkar AB, Ma Y, Dela Cruz M, Wu Y, Arechiga V, Swaminathan S, Ganz P, Wu AHB, Scherzer R, Deeks S, Hsue PY. Effect of HIV-1 Infection on Angiopoietin 1 and 2 Levels and Measures of Microvascular and Macrovascular Endothelial Dysfunction. J Am Heart Assoc 2021; 10:e021397. [PMID: 34726064 PMCID: PMC8751943 DOI: 10.1161/jaha.121.021397] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Individuals infected with HIV have an increased risk of developing cardiovascular disease; yet, the underlying mechanisms remain unknown. Recent evidence has implicated the Tie-2 tyrosine kinase receptor system and its associated ligands ANG1 (angiopoietin 1) and ANG2 (angiopoietin 2) in maintaining vascular homeostasis. In the general population, lower ANG1 levels and higher ANG2 levels are strongly correlated with the development of cardiovascular disease. In this study, we aim to investigate the associations of HIV infection with angiopoietin levels and endothelial dysfunction. Methods and Results In this cross-sectional study, we compared measures of ANG1, ANG2, and endothelial dysfunction using flow-mediated vasodilation of the brachial artery in 39 untreated subjects infected with HIV, 47 treated subjects infected with HIV, and 46 uninfected subjects from the SCOPE (Observational Study of the Consequences of the Protease Inhibitor Era) cohort. Compared with uninfected controls, treated individuals infected with HIV had 53.1% lower mean ANG1 levels (P<0.01) and similar ANG2 levels. On the other hand, untreated individuals infected with HIV had similar ANG1 levels, and 29.2% had higher ANG2 levels (P<0.01) compared with uninfected controls. When compared with individuals with untreated HIV infection, those with treated HIV infection had 56% lower ANG1 levels (P<0.01) and 22% lower ANG2 levels (P<0.01).Both treated and untreated HIV infection were associated with significant impairment in hyperemic velocity, a key measure of microvascular dysfunction (median 61 versus 72 cm/s, P<0.01), compared with uninfected controls (median 73 cm/s). This difference persisted after adjustment for ANG1 and ANG2 levels. Interestingly, when compared with untreated individuals infected with HIV, treated individuals infected with HIV had worse hyperemic velocity (-12.35 cm/s, P=0.05). In contrast, HIV status, ANG1 levels, and ANG2 levels were not associated with macrovascular dysfunction as measured by flow-mediated dilatation and brachial artery diameter, 2 other measures of vascular homeostasis. Conclusions HIV infection affects the balance between levels of ANG1 and ANG2 and may disturb endothelial homeostasis through disruption of vascular homeostasis. Individuals with treated HIV had decreased ANG1 levels and similar ANG2 levels, whereas individuals with untreated HIV had similar ANG1 levels and increased ANG2 levels, suggesting that treatment status may alter the balance between ANG1 and ANG2. HIV also promotes endothelial dysfunction via impairment of microvascular dysfunction, independent of the Tie-2 receptor system; the finding of worse microvascular dysfunction in the setting of treated HIV infection may reflect the impact of viral persistence on the microvasculature or toxicities of specific antiretroviral regimens. Further research to clarify the mechanism of HIV-mediated endothelial dysfunction is necessary to advance treatment of cardiovascular complications of HIV infection.
Collapse
Affiliation(s)
- Anjali B Thakkar
- Division of Cardiology Department of Medicine Zuckerberg San Francisco General HospitalUniversity of California San Francisco San Francisco CA
| | - Yifei Ma
- Division of Cardiology Department of Medicine Zuckerberg San Francisco General HospitalUniversity of California San Francisco San Francisco CA
| | - Mark Dela Cruz
- Section of Cardiology Department of Medicine University of Chicago Medical Center Chicago IL
| | - Yuaner Wu
- Division of Cardiology Department of Medicine Zuckerberg San Francisco General HospitalUniversity of California San Francisco San Francisco CA
| | - Victor Arechiga
- Division of Cardiology Department of Medicine Zuckerberg San Francisco General HospitalUniversity of California San Francisco San Francisco CA
| | - Shreya Swaminathan
- Division of Cardiology Department of Medicine Zuckerberg San Francisco General HospitalUniversity of California San Francisco San Francisco CA
| | - Peter Ganz
- Division of Cardiology Department of Medicine Zuckerberg San Francisco General HospitalUniversity of California San Francisco San Francisco CA
| | - Alan H B Wu
- Division of Clinical Chemistry Department of Laboratory Medicine Zuckerberg San Francisco General HospitalUniversity of California San Francisco San Francisco CA
| | - Rebecca Scherzer
- San Francisco Veteran's Affairs Medical Center San Francisco CA.,Department of Medicine University of California San Francisco CA
| | - Steven Deeks
- Positive Health Program Zuckerberg San Francisco General HospitalUniversity of California San Francisco CA
| | - Priscilla Y Hsue
- Division of Cardiology Department of Medicine Zuckerberg San Francisco General HospitalUniversity of California San Francisco San Francisco CA
| |
Collapse
|
|
15
|
Karanth SS, Sun S, Bi H, Ye K, Jin S. Angiopoietins stimulate pancreatic islet development from stem cells. Sci Rep 2021; 11:13558. [PMID: 34193893 PMCID: PMC8245566 DOI: 10.1038/s41598-021-92922-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 06/09/2021] [Indexed: 12/19/2022] Open
Abstract
In vitro differentiation of human induced pluripotent stem cells (iPSCs) into functional islets holds immense potential to create an unlimited source of islets for diabetes research and treatment. A continuous challenge in this field is to generate glucose-responsive mature islets. We herein report a previously undiscovered angiopoietin signal for in vitro islet development. We revealed, for the first time, that angiopoietins, including angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) permit the generation of islets from iPSCs with elevated glucose responsiveness, a hallmark of mature islets. Angiopoietin-stimulated islets exhibited glucose synchronized calcium ion influx in repetitive glucose challenges. Moreover, Ang2 augmented the expression of all islet hormones, including insulin, glucagon, somatostatin, and pancreatic polypeptide; and β cell transcription factors, including NKX6.1, MAFA, UCN3, and PDX1. Furthermore, we showed that the Ang2 stimulated islets were able to regulate insulin exocytosis through actin-filament polymerization and depolymerization upon glucose challenge, presumably through the CDC42-RAC1-gelsolin mediated insulin secretion signaling pathway. We also discovered the formation of endothelium within the islets under Ang2 stimulation. These results strongly suggest that angiopoietin acts as a signaling molecule to endorse in vitro islet development from iPSCs.
Collapse
Affiliation(s)
- Soujanya S Karanth
- Department of Biomedical Engineering, Binghamton University, State University of New York (SUNY), Binghamton, NY, 13902, USA
| | - Shuofei Sun
- Department of Biomedical Engineering, Binghamton University, State University of New York (SUNY), Binghamton, NY, 13902, USA
| | - Huanjing Bi
- Department of Biomedical Engineering, Binghamton University, State University of New York (SUNY), Binghamton, NY, 13902, USA
| | - Kaiming Ye
- Department of Biomedical Engineering, Binghamton University, State University of New York (SUNY), Binghamton, NY, 13902, USA.,Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), Binghamton, NY, 13902, USA
| | - Sha Jin
- Department of Biomedical Engineering, Binghamton University, State University of New York (SUNY), Binghamton, NY, 13902, USA. .,Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), Binghamton, NY, 13902, USA.
| |
Collapse
|
|
16
|
Liang G, Huang X, Hirsch J, Mehmi S, Fonda H, Chan K, Huang NF, Aalami O, Froelicher VF, Lee DP, Myers J, Lee AS, Nguyen PK. Modest Gains After an 8-Week Exercise Program Correlate With Reductions in Non-traditional Markers of Cardiovascular Risk. Front Cardiovasc Med 2021; 8:669110. [PMID: 34222367 PMCID: PMC8245677 DOI: 10.3389/fcvm.2021.669110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/13/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Although engaging in physical exercise has been shown to reduce the incidence of cardiovascular events, the molecular mechanisms by which exercise mediates these benefits remain unclear. Based on epidemiological evidence, reductions in traditional risk factors only accounts for 50% of the protective effects of exercise, leaving the remaining mechanisms unexplained. The objective of this study was to determine whether engaging in a regular exercise program in a real world clinical setting mediates cardiovascular protection via modulation of non-traditional risk factors, such as those involved in coagulation, inflammation and metabolic regulation. Methods and Results: We performed a prospective, cohort study in 52 sedentary patients with cardiovascular disease or cardiovascular risk factors at two tertiary medical centers between January 1, 2016 and December 31, 2019. Prior to and at the completion of an 8-week exercise program, we collected information on traditional cardiovascular risk factors, exercise capacity, and physical activity and performed plasma analysis to measure levels of fibrinolytic, inflammatory and metabolic biomarkers to assess changes in non-traditional cardiovascular risk factors. The median weight change, improvement in physical fitness, and change in physical activity for the entire cohort were: -4.6 pounds (IQR: +2 pounds, -11.8 pounds), 0.37 METs (IQR: -0.076 METs, 1.06 METs), and 252.7 kcals/week (IQR: -119, 921.2 kcals/week). In addition to improvement in blood pressure and cholesterol, patients who lost at least 5 pounds, expended at least 1,000 additional kcals/week, and/or achieved ≥0.5 MET increase in fitness had a significant reduction in plasminogen activator inhibitor-1 [9.07 ng/mL (95% CI: 2.78-15.35 ng/mL); P = 0.026], platelet derived growth factor beta [376.077 pg/mL (95% CI: 44.69-707.46 pg/mL); P = 0.026); and angiopoietin-1 [(1104.11 pg/mL (95% CI: 2.92-2205.30 pg/mL); P = 0.049)]. Conclusion: Modest improvements in physical fitness, physical activity, and/or weight loss through a short-term exercise program was associated with decreased plasma levels of plasminogen activator inhibitor, platelet derived growth factor beta, and angiopoietin, which have been associated with impaired fibrinolysis and inflammation.
Collapse
Affiliation(s)
- Grace Liang
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States
| | - Xianxi Huang
- Department of Critical Care Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Stanford Cardiovascular Institute, Stanford, CA, United States
| | - James Hirsch
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Sanjeev Mehmi
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Holly Fonda
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Khin Chan
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Ngan F. Huang
- Department of Cardiovascular Surgery, Stanford University, Stanford, CA, United States
| | - Oliver Aalami
- Vascular Surgery Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Victor F. Froelicher
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - David P. Lee
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States
| | - Jonathan Myers
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States
- Stanford Cardiovascular Institute, Stanford, CA, United States
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| | - Andrew S. Lee
- Stanford Cardiovascular Institute, Stanford, CA, United States
- Department of Pathology, Stanford University, Stanford, CA, United States
| | - Patricia K. Nguyen
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States
- Stanford Cardiovascular Institute, Stanford, CA, United States
- Cardiology Section, Department of Veteran Affairs, Palo Alto, CA, United States
| |
Collapse
|
|
17
|
Makowski LM, Leffers M, Waltenberger J, Pardali E. Transforming growth factor-β1 signalling triggers vascular endothelial growth factor resistance and monocyte dysfunction in type 2 diabetes mellitus. J Cell Mol Med 2021; 25:5316-5325. [PMID: 33942489 PMCID: PMC8178271 DOI: 10.1111/jcmm.16543] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 03/07/2021] [Accepted: 03/24/2021] [Indexed: 12/01/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) leads to monocyte dysfunction associated with atherogenesis and defective arteriogenesis. Transforming growth factor (TGF)-β1, placenta growth factor (PlGF)-1 and vascular endothelial growth factor (VEGF)A play important roles in atherogenesis and arteriogenesis. VEGF-receptor (VEGFR)-mediated monocyte migration is inhibited in T2DM (VEGFA resistance), while TGF-β1-induced monocyte migration is fully functional. Therefore, we hypothesize that TGF-β antagonises the VEGFA responses in human monocytes. We demonstrate that monocytes from T2DM patients have an increased migratory response towards low concentrations of TGF-β1, while PlGF-1/VEGFA responses are mitigated. Mechanistically, this is due to increased expression of type II TGF-β receptor in monocytes under high-glucose conditions and increased expression of soluble (s)VEGFR1, which is known to interfere with VEGFA signalling. VEGFA resistance in monocytes from T2DM patients can be rescued by either experimental down-regulation of TGF-β receptor expression in vitro or by functional blocking of TGF-β signalling using either a TGF-β receptor kinase inhibitor or a TGF-β neutralizing antibody. Our data demonstrate that both T2DM and high-glucose potentiate the TGF-β pathway. TGF-β signalling impairs VEGFR-mediated responses in T2DM monocytes and in this way contributes to mononuclear cell dysfunction, provide novel insights into T2DM vascular dysfunction.
Collapse
Affiliation(s)
- Lena-Maria Makowski
- Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Cardiolology, Münster, Germany
| | - Merle Leffers
- Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Cardiolology, Münster, Germany
| | - Johannes Waltenberger
- Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Cardiolology, Münster, Germany.,Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Münster, Germany.,Department of Cardiovascular Medicine, Medical Faculty, University of Münster, Münster, Germany
| | - Evangelia Pardali
- Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Cardiolology, Münster, Germany.,Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Münster, Germany
| |
Collapse
|
|
18
|
Quinaglia T, Shabani M, Breder I, Silber HA, Lima JAC, Sposito AC. Coronavirus disease-19: The multi-level, multi-faceted vasculopathy. Atherosclerosis 2021; 322:39-50. [PMID: 33706082 PMCID: PMC7883684 DOI: 10.1016/j.atherosclerosis.2021.02.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 01/28/2021] [Accepted: 02/12/2021] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIMS The new coronavirus disease (COVID-19) is a systemic disease. Mounting evidence depict signs and symptoms involving multiple organs, most of which supported by pathological data. A plausible link to these manifestations is vascular and endothelial dysfunction/damage. However, much of the current knowledge relies on opinion and incipient evidence. We aim to objectively appraise current evidence on the association between COVID-19 and vascular disease, specifically endotheliitis and vasculitis. METHODS Two researchers independently entered the search terms COVID-19 OR SARS-CoV-2 AND vasculitis, endotheliitis OR endothelium in the following online platforms: MedRxiv and LitCovid (PubMed). The search period was set from November 1, 2019 to August 28, 2020. Manuscripts with unavailable full texts, not in English, mainly on pre-clinical data, presenting only study designs or not directly related to the topics of this review were excluded. Retrospective and prospective studies, especially longitudinal ones, were given priority to the purpose of this review. Since there was paucity of prospective controlled evidence, case reports/series were also considered. RESULTS A total of 318 manuscripts were initially found. Sixty-seven (21%) were excluded: 59 (18.5%) met exclusion criteria and 8 (2.5%) were duplicates. One hundred and forty-two manuscripts (44,6%) did not provide original data and were also excluded: 35 (11%) were comments, 108 (33.9%) reviews; 1 (0.3%) position paper. One hundred and seven (33.6%) studies were considered for the present scoping review: 81 (25,5%) case reports/series; 18 (5.7%) prospective; 8 (2.5%) retrospective. Viral inclusions in endothelial cells, mononuclear cell infiltrates in the intima of small vessels and markers of endothelial cell apoptosis were demonstrated. Specificities of COVID-19 may lead to diverse vascular manifestations in different levels of the vascular bed. CONCLUSIONS Evidence indicates that COVID-19 targets vasculature and endothelium. However, high quality data is still lacking and studies with prospective designs and appropriately matched controls are needed.
Collapse
Affiliation(s)
- Thiago Quinaglia
- Discipline of Cardiology, Faculty of Medical Science - State University of Campinas - UNICAMP, Campinas, São Paulo, Brazil; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
| | - Mahsima Shabani
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Ikaro Breder
- Discipline of Cardiology, Faculty of Medical Science - State University of Campinas - UNICAMP, Campinas, São Paulo, Brazil
| | - Harry A Silber
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - João A C Lima
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Andrei C Sposito
- Discipline of Cardiology, Faculty of Medical Science - State University of Campinas - UNICAMP, Campinas, São Paulo, Brazil.
| |
Collapse
|
|
19
|
Mahtal N, Lenoir O, Tharaux PL. Glomerular Endothelial Cell Crosstalk With Podocytes in Diabetic Kidney Disease. Front Med (Lausanne) 2021; 8:659013. [PMID: 33842514 PMCID: PMC8024520 DOI: 10.3389/fmed.2021.659013] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/03/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetes is the main cause of renal failure worldwide. Complications of the kidney micro-and macro-circulation are common in diabetic patients, leading to proteinuria and can progress to end-stage renal disease. Across the complex interplays aggravating diabetes kidney disease progression, lesions of the glomerular filtration barrier appear crucial. Among its components, glomerular endothelial cells are known to be central safeguards of plasma filtration. An array of evidence has recently pinpointed its intricate relations with podocytes, highly specialized pericytes surrounding glomerular capillaries. During diabetic nephropathy, endothelial cells and podocytes are stressed and damaged. Besides, each can communicate with the other, directly affecting the progression of glomerular injury. Here, we review recent studies showing how in vitro and in vivo studies help to understand pathological endothelial cells-podocytes crosstalk in diabetic kidney disease.
Collapse
Affiliation(s)
- Nassim Mahtal
- Université de Paris, Paris Cardiovascular Center, Inserm, Paris, France
| | - Olivia Lenoir
- Université de Paris, Paris Cardiovascular Center, Inserm, Paris, France
| | | |
Collapse
|
|
20
|
Laiva AL, O’Brien FJ, Keogh MB. SDF-1α Gene-Activated Collagen Scaffold Restores Pro-Angiogenic Wound Healing Features in Human Diabetic Adipose-Derived Stem Cells. Biomedicines 2021; 9:biomedicines9020160. [PMID: 33562165 PMCID: PMC7914837 DOI: 10.3390/biomedicines9020160] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/17/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023] Open
Abstract
Non-healing diabetic foot ulcers (DFUs) can lead to leg amputation in diabetic patients. Autologous stem cell therapy holds some potential to solve this problem; however, diabetic stem cells are relatively dysfunctional and restrictive in their wound healing abilities. This study sought to explore if a novel collagen-chondroitin sulfate (coll-CS) scaffold, functionalized with polyplex nanoparticles carrying the gene encoding for stromal-derived factor-1 alpha (SDF-1α gene-activated scaffold), can enhance the regenerative functionality of human diabetic adipose-derived stem cells (ADSCs). We assessed the impact of the gene-activated scaffold on diabetic ADSCs by comparing their response against healthy ADSCs cultured on a gene-free scaffold over two weeks. Overall, we found that the gene-activated scaffold could restore the pro-angiogenic regenerative response in the human diabetic ADSCs similar to the healthy ADSCs on the gene-free scaffold. Gene and protein expression analysis revealed that the gene-activated scaffold induced the overexpression of SDF-1α in diabetic ADSCs and engaged the receptor CXCR7, causing downstream β-arrestin signaling, as effectively as the transfected healthy ADSCs. The transfected diabetic ADSCs also exhibited pro-wound healing features characterized by active matrix remodeling of the provisional fibronectin matrix and basement membrane protein collagen IV. The gene-activated scaffold also induced a controlled pro-healing response in the healthy ADSCs by disabling early developmental factors signaling while promoting the expression of tissue remodeling components. Conclusively, we show that the SDF-1α gene-activated scaffold can overcome the deficiencies associated with diabetic ADSCs, paving the way for autologous stem cell therapies combined with novel biomaterials to treat DFUs.
Collapse
Affiliation(s)
- Ashang L. Laiva
- Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland; (A.L.L.); (F.J.O.)
- Department of Biomedical Science, Royal College of Surgeons in Ireland, Adliya, P.O. Box 15503 Manama, Bahrain
| | - Fergal J. O’Brien
- Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland; (A.L.L.); (F.J.O.)
- Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
- Advanced Materials and Bioengineering Research Centre, Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin 2, Ireland
| | - Michael B. Keogh
- Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland; (A.L.L.); (F.J.O.)
- Department of Biomedical Science, Royal College of Surgeons in Ireland, Adliya, P.O. Box 15503 Manama, Bahrain
- Correspondence: ; Tel.: +973-17351450
| |
Collapse
|
|
21
|
Mercier C, Rousseau M, Geraldes P. Growth Factor Deregulation and Emerging Role of Phosphatases in Diabetic Peripheral Artery Disease. Front Cardiovasc Med 2021; 7:619612. [PMID: 33490120 PMCID: PMC7817696 DOI: 10.3389/fcvm.2020.619612] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/10/2020] [Indexed: 01/25/2023] Open
Abstract
Peripheral artery disease is caused by atherosclerosis of lower extremity arteries leading to the loss of blood perfusion and subsequent critical ischemia. The presence of diabetes mellitus is an important risk factor that greatly increases the incidence, the progression and the severity of the disease. In addition to accelerated disease progression, diabetic patients are also more susceptible to develop serious impairment of their walking abilities through an increased risk of lower limb amputation. Hyperglycemia is known to alter the physiological development of collateral arteries in response to ischemia. Deregulation in the production of several critical pro-angiogenic factors has been reported in diabetes along with vascular cell unresponsiveness in initiating angiogenic processes. Among the multiple molecular mechanisms involved in the angiogenic response, protein tyrosine phosphatases are potent regulators by dephosphorylating pro-angiogenic tyrosine kinase receptors. However, evidence has indicated that diabetes-induced deregulation of phosphatases contributes to the progression of several micro and macrovascular complications. This review provides an overview of growth factor alterations in the context of diabetes and peripheral artery disease, as well as a description of the role of phosphatases in the regulation of angiogenic pathways followed by an analysis of the effects of hyperglycemia on the modulation of protein tyrosine phosphatase expression and activity. Knowledge of the role of phosphatases in diabetic peripheral artery disease will help the development of future therapeutics to locally regulate phosphatases and improve angiogenesis.
Collapse
Affiliation(s)
- Clément Mercier
- Department of Medicine, Division of Endocrinology, Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Marina Rousseau
- Department of Medicine, Division of Endocrinology, Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Pedro Geraldes
- Department of Medicine, Division of Endocrinology, Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada
| |
Collapse
|
|
22
|
Hayashi SI, Rakugi H, Morishita R. Insight into the Role of Angiopoietins in Ageing-Associated Diseases. Cells 2020; 9:E2636. [PMID: 33302426 PMCID: PMC7762563 DOI: 10.3390/cells9122636] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 12/05/2020] [Accepted: 12/07/2020] [Indexed: 12/17/2022] Open
Abstract
Angiopoietin (Ang) and its receptor, TIE signaling, contribute to the development and maturation of embryonic vasculature as well as vascular remodeling and permeability in adult tissues. Targeting both this signaling pathway and the major pathway with vascular endothelial growth factor (VEGF) is expected to permit clinical applications, especially in antiangiogenic therapies against tumors. Several drugs targeting the Ang-TIE signaling pathway in cancer patients are under clinical development. Similar to how cancer increases with age, unsuitable angiogenesis or endothelial dysfunction is often seen in other ageing-associated diseases (AADs) such as atherosclerosis, Alzheimer's disease, type 2 diabetes, chronic kidney disease and cardiovascular diseases. Thus, the Ang-TIE pathway is a possible molecular target for AAD therapy. In this review, we focus on the potential role of the Ang-TIE signaling pathway in AADs, especially non-cancer-related AADs. We also suggest translational insights and future clinical applications of this pathway in those AADs.
Collapse
Affiliation(s)
- Shin-ichiro Hayashi
- Department of Clinical Gene Therapy, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Hiromi Rakugi
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan;
| | - Ryuichi Morishita
- Department of Clinical Gene Therapy, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| |
Collapse
|
|
23
|
Valipour E, Nooshabadi VT, Mahdipour S, Shabani S, Farhady-Tooli L, Majidian S, Noroozi Z, Mansouri K, Motevaseli E, Modarressi MH. Anti-angiogenic effects of testis-specific gene antigen 10 on primary endothelial cells. Gene 2020; 754:144856. [PMID: 32512160 DOI: 10.1016/j.gene.2020.144856] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 05/24/2020] [Accepted: 06/04/2020] [Indexed: 01/08/2023]
Abstract
Growing evidence indicates the antitumor and antiangiogenesis activities of testis-specific gene antigen 10 (TSGA10). However, the underlying mechanisms and precise role of TSGA10 in angiogenesis are still elusive. In this study, we isolated human umbilical cord vein endothelial cells (HUVECs) and stably transfected with pcDNA3.1 carrying TSGA10 coding sequence. We demonstrated that TSGA10 over-expression significantly decreases HUVEC tubulogenesis and interconnected capillary network formation. HUVECs over-expressing TSGA10 exhibited a significant decrease in migration and proliferation rates. TSGA10 over-expression markedly decreased expression of angiogenesis-related genes, including VEGF-A, VEGFR-2, Ang-1, Ang-2, and Tie-2. Our ELISA results showed the decrease in VEGF-A mRNA expression level is associated with a significant decrease in its protein secretion. Additionally, over-expressing TSGA10 decreased expression levels of marker genes of cell migration (MMP-2, MMP-9, and SDF-1a) and proliferation (PCNA and Ki-67. Furthermore, ERK-1 and AKT phosphorylation significantly reduced in HUVECs over-expressing TSGA10. Our findings suggest a potent anti-angiogenesis activity of TSGA10 in HUVECs through down-regulation of ERK and AKT signalling pathways, and may provide therapeutic benefits for the management of different pathological angiogenesis.
Collapse
Affiliation(s)
- Elahe Valipour
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Vajihe Taghdiri Nooshabadi
- Department of Tissue Engineering and Applied Cell Sciences, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Shadi Mahdipour
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sasan Shabani
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Farhady-Tooli
- Department of Microbiology, School of Biology, College of Science, Tehran University, Tehran, Iran
| | - Sina Majidian
- School of Electrical Engineering, Iran University of Science and Technology, Tehran, Iran
| | - Zahra Noroozi
- Department of Molecular Medicine, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Elaheh Motevaseli
- Department of Molecular Medicine, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran
| | | |
Collapse
|
|
24
|
Tian M, Carroll LS, Tang L, Uehara H, Westenfelder C, Ambati BK, Huang Y. Systemic AAV10.COMP-Ang1 rescues renal glomeruli and pancreatic islets in type 2 diabetic mice. BMJ Open Diabetes Res Care 2020; 8:8/1/e000882. [PMID: 32792355 PMCID: PMC7430492 DOI: 10.1136/bmjdrc-2019-000882] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 02/05/2020] [Accepted: 06/14/2020] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Diabetic hyperglycemia causes progressive and generalized damage to the microvasculature. In renal glomeruli, this results in the loss of podocytes with consequent loss of constitutive angiopoietin-1 (Ang1) signaling, which is required for stability of the glomerular endothelium. Repeated tail vein injection of adenovirus expressing COMP-Ang1 (a stable bioengineered form of Ang1) was previously reported to improve diabetic glomerular damage despite the liver and lungs being primary targets of adenoviral infection. We thus hypothesized that localizing delivery of sustained COMP-Ang1 to the kidney could increase its therapeutic efficacy and safety for the treatment of diabetes. RESEARCH DESIGN AND METHODS Using AAVrh10 adeno-associated viral capsid with enhanced kidney tropism, we treated 10-week-old uninephrectomized db/db mice (a model of type 2 diabetes) with a single dose of AAVrh10.COMP-Ang1 delivered via the intracarotid artery, compared with untreated diabetic db/db control and non-diabetic db/m mice. RESULTS Surprisingly, both glomerular and pancreatic capillaries expressed COMP-Ang1, compensating for diabetes-induced loss of tissue Ang1. Importantly, treatment with AAVrh10.COMP-Ang1 yielded a significant reduction of glycemia (blood glucose, 241±193 mg/dL vs 576±31 mg/dL; glycosylated hemoglobin, 7.2±1.5% vs 11.3±1.3%) and slowed the progression of albuminuria and glomerulosclerosis in db/db mice by 70% and 61%, respectively, compared with untreated diabetic db/db mice. Furthermore, COMP-Ang1 ameliorated diabetes-induced increases of NF-kBp65, nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-2 (Nox2), p47phox and productions of myeloperoxidase, the inflammatory markers in both renal and pancreatic tissues, and improved beta-cell density in pancreatic islets. CONCLUSIONS These results highlight the potential of localized Ang1 therapy for treatment of diabetic visceropathies and provide a mechanistic explanation for reported improvements in glucose control via Ang1/Tie2 signaling in the pancreas.
Collapse
Affiliation(s)
- Mi Tian
- Internal Medicine/Nephrology, University of Utah, Salt Lake City, Utah, USA
- Internal Medicine/Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lara S Carroll
- Ophthalmology and Visual Science, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA
| | - Li Tang
- Internal Medicine/Nephrology, University of Utah, Salt Lake City, Utah, USA
| | - Hironori Uehara
- Ophthalmology and Visual Science, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA
| | | | - Balamurali K Ambati
- Ophthalmology and Visual Science, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA
| | - Yufeng Huang
- Internal Medicine/Nephrology, University of Utah, Salt Lake City, Utah, USA
| |
Collapse
|
|
25
|
Herrera J, Bockhorst K, Bhattarai D, Uray K. Gastrointestinal vascular permeability changes following spinal cord injury. Neurogastroenterol Motil 2020; 32:e13834. [PMID: 32163655 DOI: 10.1111/nmo.13834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 02/06/2020] [Accepted: 02/18/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Gastrointestinal (GI) dysfunction is observed clinically after spinal cord injury (SCI) and contributes to the diminished long-term quality of life. Our study examined the acute and chronic GI vascular changes that occur following SCI. We demonstrated that the GI vascular tract in SCI mice becomes compromised during the acute phase of injury and persists into the chronic phase of injury. METHODS Gastrointestinal vasculature permeability was measured using dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) at 48 hours, and 2 and 4 weeks following contusion spinal cord injury. Angiopoietin-1, a vascular stabilizing protein, was administered intravenously following injury. Intestinal contractile activity assessments were performed following the last imaging session. KEY RESULTS Our results indicated that a single administration of Ang-1 reduced vascular permeability at 48 hours but the effect was only transient. However, when the treatment paradigm was changed from a single administration to multiple administrations of Ang-1 following contusion injury, our DCE MRI data indicated a significant decrease in GI vascular permeability 4 weeks after injury compared with vehicle control treated animals. This improved GI vascular permeability was associated with improved sustained intestinal contractile activity. We also demonstrated that Ang-1 reduced the expression of sICAM-1 in the ileum compared with the saline-treated group. CONCLUSIONS AND INFERENCES We show that the GI vasculature is compromised in the acute and chronic phase of injury following spinal contusion. Our results also indicate that multiple administrations of Ang-1 can attenuate GI vascular permeability, possibly reduce inflammation, and improve sustained agonist-induced contraction compared with saline treatment.
Collapse
Affiliation(s)
- Juan Herrera
- Diagnostic and Interventional Imaging, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Kurt Bockhorst
- Diagnostic and Interventional Imaging, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Deepa Bhattarai
- Pediatric Surgery University of Texas Medical School at Houston, Houston, Texas, USA
| | - Karen Uray
- Pediatric Surgery University of Texas Medical School at Houston, Houston, Texas, USA.,Medicinal Chemistry, University of Debrecen, Debrecen, Hungary
| |
Collapse
|
|
26
|
Sokolovska J, Stefanovics J, Gersone G, Pahirko L, Valeinis J, Kalva-Vaivode S, Rovite V, Blumfelds L, Pirags V, Tretjakovs P. Angiopoietin 2 and Neuropeptide Y are Associated with Diabetic Kidney Disease in Type 1 Diabetes Mellitus. Exp Clin Endocrinol Diabetes 2020; 128:654-662. [PMID: 31958847 DOI: 10.1055/a-1079-4711] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Serum angiopoietin 2 levels have been associated with endothelial dysfunction and diabetic kidney disease. Derangements in autonomous nervous system lead to increased production of vasoconstrictory and angiogenic mediators such as norepinephrine and neuropeptide Y and are associated with increased risk of microvascular complications. AIM To investigate associations between angiopoietin 2, neuropeptide Y and diabetic kidney disease in patients with type 1 diabetes mellitus. METHODS 289 patients with type 1 diabetes mellitus duration > 1 year were included. Patients were stratified according to presence of diabetic nephropathy (macroalbuminuria, estimated glomerular filtration rate<60 ml/min/1.73 m2 or end-stage renal disease). Angiopoietin 2 was measured by Luminex technology. Neuropeptide Y was measured by ELISA. RESULTS Patients with diabetic nephropathy had significantly increased levels of angiopoietin 2 (4020.5 (2172.4-5778.1) pg/ml vs. 2001.0 (1326.7-2862.7) pg/ml) and neuropeptide Y (18.22 (14.85-21.85) ng/ml vs. 12.91 (9.96-17.07) ng/ml). Higher levels of angiopoietin 2 and neuropeptide Y were observed also in patients with arterial hypertension. Angiopoietin 2 and neuropeptide Y correlated significantly (ρ=0.245, p<0.001). Both biomarkers were significant predictors of estimated glomerular filtration rate and diabetic nephropathy in univariate regression models. In the fully adjusted regression models and after application of a stepwise selection regression method, angiopoietin 2 demonstrated a stronger predictive power for diabetic nephropathy compared to neuropeptide Y. CONCLUSION Diabetic nephropathy is associated with increased serum concentrations of angiopoietin 2 (marker of endothelial dysfunction) and neuropeptide Y (marker of sympathetic activity) in type 1 diabetes. Angiopoietin 2 is a more potent predictor of diabetic nephropathy compared to neuropeptide Y.
Collapse
Affiliation(s)
| | | | - Gita Gersone
- Faculty of Medicine, Department of Human Physiology and Biochemistry, Riga Stradins University, Latvia
| | - Leonora Pahirko
- Faculty of Physics, Mathematics and Optometry, University of Latvia, Riga, Latvia
| | - Janis Valeinis
- Faculty of Physics, Mathematics and Optometry, University of Latvia, Riga, Latvia
| | | | - Vita Rovite
- Latvian Biomedical Research and Study Centre, Riga, Latvia
| | - Leons Blumfelds
- Faculty of Medicine, Department of Human Physiology and Biochemistry, Riga Stradins University, Latvia
| | - Valdis Pirags
- Faculty of Medicine, University of Latvia, Riga, Latvia.,Pauls Stradins Clinical University Hospital, Riga, Latvia.,Latvian Biomedical Research and Study Centre, Riga, Latvia
| | - Peteris Tretjakovs
- Faculty of Medicine, Department of Human Physiology and Biochemistry, Riga Stradins University, Latvia
| |
Collapse
|
|
27
|
Peng X, Wang X, Fan M, Zhao J, Lin L, Liu J. Plasma levels of von Willebrand factor in type 2 diabetes patients with and without cardiovascular diseases: A meta-analysis. Diabetes Metab Res Rev 2020; 36:e3193. [PMID: 31145835 DOI: 10.1002/dmrr.3193] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 05/17/2019] [Accepted: 05/24/2019] [Indexed: 01/18/2023]
Abstract
Chronic vascular complications are the major causes of death and disability of type 2 diabetes mellitus (T2DM) patients. von Willebrand factor (vWF) is involved in pathogenesis of cardiovascular diseases (CVD). Previous studies showed elevated plasma levels of vWF in T2DM patients with CVD, but the association has not been validated. The aim of this meta-analysis was to compare plasma levels of vWF in T2DM patients with and without CVD. We performed a meta-analysis based on published case-control studies of vWF in T2DM patients with and without CVD indexed in PubMed and other databases updated to April 2018. After independently assessing methodological quality and extracting data, 9 eligible studies were obtained including 576 cases and 632 controls. The standard mean difference (SMD) and 95% confidence intervals (95% CI) were calculated using random-effects model. Meta-analysis showed that plasma level of vWF was significantly higher in T2DM patients with CVD than T2DM patients without CVD (SMD = 0.61; 95% CI, 0.32-0.90; P < .00001). Subgroup and sensitivity analyses confirmed the robustness of the results. Plasma levels of vWF are significantly elevated in patients with T2DM complicated by CVD. This study helps further characterize the prognostic value of vWF for cardiovascular complications in T2DM patients.
Collapse
Affiliation(s)
- Xun Peng
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
- Graduate School, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Xia Wang
- School of Medicine, Shandong University, Jinan, China
| | - Mengge Fan
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
- Graduate School, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Junyu Zhao
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
| | - Liao Lin
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
| | - Ju Liu
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
| |
Collapse
|
|
28
|
Zhang W, Tang XH, Zhang JJ, He Q. miR145 Regulates the Proliferation and Apoptosis of Rat Vascular Endothelial Cells under Hyperglycemia by Targeting the ANGPT2 Gene and Involving the NFκB Signaling Pathway. Diabetes Metab Syndr Obes 2020; 13:4435-4446. [PMID: 33239896 PMCID: PMC7680677 DOI: 10.2147/dmso.s273451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/14/2020] [Indexed: 01/31/2023] Open
Abstract
PURPOSE A majority of diabetes mellitus patients with disturbances of glucose metabolism present with vascular complications. This study aimed to explore regulatory mechanisms of miR145 and its potential target gene ANGPT2 on diabetic vasculopathy under hyperglycemia. METHODS Based on the fact that miR145 is detected in rat aortic endothelial cells (RAECs) under hyperglycemia, RAECs were transfected with miR145 mimics/inhibitor for further confirmation. RAEC proliferation was detected with CCK8 assays, and cell apoptosis and CD34+-cell population with annexinV-PI staining and anti-CD34FITC on flow cytometry, respectively. Then, qPCR and Western blot were applied to detect mRNA and protein expression of ANGPT2 and involved pathway factor NFκB p65. Subsequently, dual luciferase-reporter gene analysis was utilized to verify whether miR145 acted directly upon the 3'UTR of ANGPT2 mRNA. RESULTS The ANGPT2 gene was confirmed to be a direct target of miR145. miR145 mimics markedly downregulated the expression of ANGPT2 and NFκB p65, boosted the percentage of the CD34+ phenotype, and promoted proliferation and suppressed apoptosis of RAECs under hyperglycemia. CONCLUSION miR145 might regulate the viability of RAECs via targeting ANGPT2 and involving NFκB signaling to exert a protective effect on diabetic vasculature.
Collapse
Affiliation(s)
- Wen Zhang
- Clinical Medical Research Center and Yunnan Provincial Key Laboratory of Clinical Virology (2018DG010), First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan650032, People’s Republic of China
| | - Xin-Hua Tang
- Center of Genetic Diagnosis, First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan650032, People’s Republic of China
| | - Jin-Juan Zhang
- Kunming Institute of Zoology, Chinese Academy of Science (CAS), Kunming, Yunnan, 650223, People’s Republic of China
| | - Quan He
- Emergency Department, First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650032, People's Republic of China
- Correspondence: Quan He Emergency Department, First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, 157 Jinbi Road, Xishan District, Kunming650032, Yunnan Province, People’s Republic of ChinaTel +86 871 6363 9921Fax +86 871 6362 7731 Email
| |
Collapse
|
|
29
|
Nevi L, Costantini D, Safarikia S, Di Matteo S, Melandro F, Berloco PB, Cardinale V. Cholest-4,6-Dien-3-One Promote Epithelial-To-Mesenchymal Transition (EMT) in Biliary Tree Stem/Progenitor Cell Cultures In Vitro. Cells 2019; 8:cells8111443. [PMID: 31731674 PMCID: PMC6912632 DOI: 10.3390/cells8111443] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/31/2019] [Accepted: 11/11/2019] [Indexed: 12/12/2022] Open
Abstract
Human biliary tree stem/progenitor cells (hBTSCs), reside in peribiliary glands, are mainly stimulated by primary sclerosing cholangitis (PSC) and cholangiocarcinoma. In these pathologies, hBTSCs displayed epithelial-to-mesenchymal transition (EMT), senescence characteristics, and impaired differentiation. Here, we investigated the effects of cholest-4,6-dien-3-one, an oxysterol involved in cholangiopathies, on hBTSCs biology. hBTSCs were isolated from donor organs, cultured in self-renewal control conditions, differentiated in mature cholangiocytes by specifically tailored medium, or exposed for 10 days to concentration of cholest-4,6-dien-3-one (0.14 mM). Viability, proliferation, senescence, EMT genes expression, telomerase activity, interleukin 6 (IL6) secretion, differentiation capacity, and HDAC6 gene expression were analyzed. Although the effect of cholest-4,6-dien-3-one was not detected on hBTSCs viability, we found a significant increase in cell proliferation, senescence, and IL6 secretion. Interestingly, cholest-4.6-dien-3-one impaired differentiation in mature cholangiocytes and, simultaneously, induced the EMT markers, significantly reduced the telomerase activity, and induced HDAC6 gene expression. Moreover, cholest-4,6-dien-3-one enhanced bone morphogenic protein 4 (Bmp-4) and sonic hedgehog (Shh) pathways in hBTSCs. The same pathways activated by human recombinant proteins induced the expression of EMT markers in hBTSCs. In conclusion, we demonstrated that chronic exposition of cholest-4,6-dien-3-one induced cell proliferation, EMT markers, and senescence in hBTSC, and also impaired the differentiation in mature cholangiocytes.
Collapse
Affiliation(s)
- Lorenzo Nevi
- Department of Translation and Precision Medicine, “Sapienza” University of Rome, 00185 Rome, Italy; (D.C.); (S.S.); (S.D.M.)
- Correspondence: (L.N.); (V.C.); Tel.: +39-3392335294 (L.N.); +39-3495601492 (V.C.)
| | - Daniele Costantini
- Department of Translation and Precision Medicine, “Sapienza” University of Rome, 00185 Rome, Italy; (D.C.); (S.S.); (S.D.M.)
| | - Samira Safarikia
- Department of Translation and Precision Medicine, “Sapienza” University of Rome, 00185 Rome, Italy; (D.C.); (S.S.); (S.D.M.)
| | - Sabina Di Matteo
- Department of Translation and Precision Medicine, “Sapienza” University of Rome, 00185 Rome, Italy; (D.C.); (S.S.); (S.D.M.)
| | - Fabio Melandro
- Department of General Surgery and Organ Transplantation, Sapienza University of Rome, 0016 Rome, Italy; (F.M.); (P.B.B.)
| | - Pasquale Bartolomeo Berloco
- Department of General Surgery and Organ Transplantation, Sapienza University of Rome, 0016 Rome, Italy; (F.M.); (P.B.B.)
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, “Sapienza” University of Rome, 04100 Latina, Italy
- Correspondence: (L.N.); (V.C.); Tel.: +39-3392335294 (L.N.); +39-3495601492 (V.C.)
| |
Collapse
|
|
30
|
Barchetta I, Cimini FA, Ciccarelli G, Baroni MG, Cavallo MG. Sick fat: the good and the bad of old and new circulating markers of adipose tissue inflammation. J Endocrinol Invest 2019; 42:1257-1272. [PMID: 31073969 DOI: 10.1007/s40618-019-01052-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 04/29/2019] [Indexed: 01/08/2023]
Abstract
Adipose tissue (AT) is one of the largest endocrine organs contributing to metabolic homeostasis. The functional pleiotropism of AT depends on its ability to secrete a large number of hormones, cytokines, extracellular matrix proteins and growth factors, all influencing many local and systemic physiological and pathophysiological processes. In condition of chronic positive energy balance, adipocyte expansion, hypoxia, apoptosis and stress all lead to AT inflammation and dysfunction, and it has been demonstrated that this sick fat is a main risk factor for many metabolic disorders, such as type 2 diabetes mellitus, fatty liver, cardiovascular disease and cancer. AT dysfunction is tightly associated with aberrant secretion of bioactive peptides, the adipocytokines, and their blood concentrations often reflect the expression in the AT. Despite the existence of an association between AT dysfunction and systemic pro-inflammatory state, most of the circulating molecules detectable in obese and dysmetabolic individuals do not identify specifically the condition of sick fat. Based on this premise, this review provides a concise overview of "classic" and novel promising adipocytokines associated with AT inflammation and discusses possible critical approaches to their interpretation in clinical practice.
Collapse
Affiliation(s)
- I Barchetta
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161, Rome, Italy
| | - F A Cimini
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161, Rome, Italy
| | - G Ciccarelli
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161, Rome, Italy
| | - M G Baroni
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161, Rome, Italy.
| | - M G Cavallo
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161, Rome, Italy.
| |
Collapse
|
|
31
|
Schacher NM, Raaz-Schrauder D, Pasutto F, Stumpfe FM, Tauchi M, Dietel B, Achenbach S, Urschel K. Impact of single nucleotide polymorphisms in the VEGFR2 gene on endothelial cell activation under non‑uniform shear stress. Int J Mol Med 2019; 44:1366-1376. [PMID: 31432097 PMCID: PMC6713417 DOI: 10.3892/ijmm.2019.4301] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 06/26/2019] [Indexed: 12/20/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor receptor 2 (VEGFR2) are associated with coronary artery disease, hypertension and myocardial infarction. However, their association with atherosclerosis remains to be fully elucidated. The purpose of the present study was to determine whether SNPs are involved in atherogenesis, by analyzing their impact on human umbilical vein endothelial cells (HUVECs) under laminar and non‑uniform shear stress in a well‑established in vitro model that simulates shear stress‑induced proatherogenic processes at vessel bifurcations. All experiments were performed using freshly isolated HUVECs. Three SNPs in the VEGFR2 gene (rs1870377 T>A, rs2071559 A>G and rs2305948 C>T) were genotyped and the expression levels of VEGFR2 were semi‑quantitatively determined using western blotting. Subsequently, the HUVECs were seeded in bifurcating flow‑through cell culture slides and flow (9.6 ml/min) was applied for 19 h, including tumor necrosis factor‑α stimulation during the final 2 h of flow. The protein expression levels of VCAM‑1, E‑selectin and VEGFR2 and the adhesion of THP‑1 cells were analyzed in laminar and non‑uniform shear stress regions. Data were analyzed for associations with the respective SNPs. The total expression of VEGFR2 was significantly lower under non‑uniform shear stress than under laminar shear stress conditions, independent of the genotype. The expression of VEGFR2 between the different shear stress patterns was not significantly altered by the different SNPs. The expression levels of VCAM‑1 and E‑selectin were lower in the A/A genotype compared with those in other genotypes in rs1870377 T>A and rs2071559 A>G. In conclusion, the results suggested that SNPs within the VEGFR2 gene have a significant impact on shear stress‑related endothelial activation.
Collapse
Affiliation(s)
- Nora M Schacher
- Department of Medicine 2‑Cardiology and Angiology, Erlangen University Hospital, Friedrich‑Alexander University Erlangen‑Nürnberg, D‑91054 Erlangen, Germany
| | - Dorette Raaz-Schrauder
- Department of Medicine 2‑Cardiology and Angiology, Erlangen University Hospital, Friedrich‑Alexander University Erlangen‑Nürnberg, D‑91054 Erlangen, Germany
| | - Francesca Pasutto
- Institute of Human Genetics, Friedrich‑Alexander University Erlangen‑Nürnberg, D‑91051 Erlangen, Germany
| | - Florian M Stumpfe
- Department of Obstetrics and Gynecology, Erlangen University Hospital, Comprehensive Cancer Center Erlangen‑EMN, Friedrich‑Alexander University Erlangen‑Nürnberg, D‑91054 Erlangen, Germany
| | - Miyuki Tauchi
- Department of Medicine 2‑Cardiology and Angiology, Erlangen University Hospital, Friedrich‑Alexander University Erlangen‑Nürnberg, D‑91054 Erlangen, Germany
| | - Barbara Dietel
- Department of Medicine 2‑Cardiology and Angiology, Erlangen University Hospital, Friedrich‑Alexander University Erlangen‑Nürnberg, D‑91054 Erlangen, Germany
| | - Stephan Achenbach
- Department of Medicine 2‑Cardiology and Angiology, Erlangen University Hospital, Friedrich‑Alexander University Erlangen‑Nürnberg, D‑91054 Erlangen, Germany
| | - Katharina Urschel
- Department of Medicine 2‑Cardiology and Angiology, Erlangen University Hospital, Friedrich‑Alexander University Erlangen‑Nürnberg, D‑91054 Erlangen, Germany
| |
Collapse
|
|
32
|
Scurt FG, Menne J, Brandt S, Bernhardt A, Mertens PR, Haller H, Chatzikyrkou C. Systemic Inflammation Precedes Microalbuminuria in Diabetes. Kidney Int Rep 2019; 4:1373-1386. [PMID: 31701047 PMCID: PMC6829192 DOI: 10.1016/j.ekir.2019.06.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/22/2019] [Accepted: 06/03/2019] [Indexed: 12/13/2022] Open
Abstract
Aim The aim of the case-control study was to investigate if serum biomarkers indicative of vascular inflammation and endothelial dysfunction can predict the development of microalbuminuria in patients with diabetes mellitus type 2. Methods Among participants enrolled in the ROADMAP (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention) and observational follow-up (OFU) studies, a panel of 15 serum biomarkers was quantified from samples obtained at initiation of the study and tested for associations with the development of new-onset microalbuminuria during follow-up. A case-control study was conducted with inclusion of 172 patients with microalbuminuria and 188 matched controls. Nonparametric inferential, nonlinear regression, mediation, and bootstrapping statistical methods were used for the analysis. Results The median follow-up time was 37 months. At baseline, mean concentrations of C-X-C motif chemokine ligand 16 (CXCL-16), transforming growth factor (TGF)–β1 and angiopoietin-2 were higher in patients with subsequent microalbuminuria. In the multivariate analysis, after adjustment for age, sex, body mass index, glycated hemoglobin, duration of diabetes, low-density lipoprotein (LDL), smoking status, blood pressure, baseline urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), time of follow-up and cardiovascular disease, CXCL-16 (odds ratio [OR] 2.60, 95% confidence interval [CI] 1.71–3.96), angiopoietin-2 (OR 1.50, 95% CI 1.14–1.98) and TGF-β1 (OR 1.03, 95% CI 1.01–1.04) remained significant predictors of new-onset microalbuminuria (P < 0.001). Inclusion of these biomarkers in conventional clinical risk models for prediction of microalbuminuria increased the area under the curve (AUC) from 0.638 to 0.760 (P < 0.001). Conclusion In patients with type 2 diabetes, elevated plasma levels of CXCL-16, angiopoietin-2, and TGF-β1 are independently predictive of microalbuminuria. Thus, these serum markers improve renal risk models beyond established clinical risk factors.
Collapse
Affiliation(s)
- Florian G Scurt
- Clinic of Nephrology, Hypertension, Diabetes and Endocrinology, Health Campus Immunology, Infectiology, and Inflammation, Otto-von-Guericke University, Magdeburg, Germany
| | - Jan Menne
- Nephrology Section, Hanover Medical School, Hanover, Germany
| | - Sabine Brandt
- Clinic of Nephrology, Hypertension, Diabetes and Endocrinology, Health Campus Immunology, Infectiology, and Inflammation, Otto-von-Guericke University, Magdeburg, Germany
| | - Anja Bernhardt
- Clinic of Nephrology, Hypertension, Diabetes and Endocrinology, Health Campus Immunology, Infectiology, and Inflammation, Otto-von-Guericke University, Magdeburg, Germany
| | - Peter R Mertens
- Clinic of Nephrology, Hypertension, Diabetes and Endocrinology, Health Campus Immunology, Infectiology, and Inflammation, Otto-von-Guericke University, Magdeburg, Germany
| | - Hermann Haller
- Nephrology Section, Hanover Medical School, Hanover, Germany
| | - Christos Chatzikyrkou
- Clinic of Nephrology, Hypertension, Diabetes and Endocrinology, Health Campus Immunology, Infectiology, and Inflammation, Otto-von-Guericke University, Magdeburg, Germany.,Nephrology Section, Hanover Medical School, Hanover, Germany
| | | |
Collapse
|
|
33
|
McCarthy CP, Shrestha S, Ibrahim N, van Kimmenade RRJ, Gaggin HK, Mukai R, Magaret C, Barnes G, Rhyne R, Garasic JM, Januzzi JL. Performance of a clinical/proteomic panel to predict obstructive peripheral artery disease in patients with and without diabetes mellitus. Open Heart 2019; 6:e000955. [PMID: 31217993 PMCID: PMC6546197 DOI: 10.1136/openhrt-2018-000955] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 03/21/2019] [Accepted: 04/14/2019] [Indexed: 02/07/2023] Open
Abstract
Background Patients with diabetes mellitus (DM) are at substantial risk of developing peripheral artery disease (PAD). We recently developed a clinical/proteomic panel to predict obstructive PAD. In this study, we compare the accuracy of this panel for the diagnosis of PAD in patients with and without DM. Methods and results The HART PAD panel consists of one clinical variable (history of hypertension) and concentrations of six biomarkers (midkine, kidney injury molecule-1, interleukin-23, follicle-stimulating hormone, angiopoietin-1 and eotaxin-1). In a prospective cohort of 354 patients undergoing peripheral and/or coronary angiography, performance of this diagnostic panel to detect ≥50% stenosis in at least one peripheral vessel was assessed in patients with (n=94) and without DM (n=260). The model had an area under the receiver operating characteristic curve (AUC) of 0.85 for obstructive PAD. At optimal cut-off, the model had 84% sensitivity, 75% specificity, positive predictive value (PPV) of 84% and negative predictive value (NPV) of 75% for detection of PAD among patients with DM, similar as in those without DM. In those with DM, partitioning the model into five levels resulted in a PPV of 95% and NPV of 100% in the highest and lowest levels, respectively. Abnormal scores were associated with a shorter time to revascularisation during 4.3 years of follow-up. Conclusion A clinical/biomarker model can predict with high accuracy the presence of PAD among patients with DM. Trial registration number NCT00842868.
Collapse
Affiliation(s)
- Cian P McCarthy
- Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Shreya Shrestha
- Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Nasrien Ibrahim
- Medicine/Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | | | - Hanna K Gaggin
- Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Renata Mukai
- Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | | | | | | | - Joseph M Garasic
- Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - James L Januzzi
- Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA
| |
Collapse
|
|
34
|
Michalska-Jakubus M, Cutolo M, Smith V, Krasowska D. Imbalanced serum levels of Ang1, Ang2 and VEGF in systemic sclerosis: Integrated effects on microvascular reactivity. Microvasc Res 2019; 125:103881. [PMID: 31075243 DOI: 10.1016/j.mvr.2019.103881] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 02/03/2019] [Accepted: 05/04/2019] [Indexed: 11/30/2022]
Abstract
INTRODUCTION AND AIM Microangiopathy is a hallmark of systemic sclerosis (SSc). It is a progressive process from an early inflammatory and proangiogenic environment to insufficient microvascular repair with loss of microvessels. The exact underlying mechanisms remain ill-defined. Aim of the study was to investigate whether imbalanced angiopoietins/VEGF serum profile should be related in SSc to the altered microvascular reactivity characterized by aberrant angiogenesis and avascularity. MATERIALS AND METHODS Serum levels of Angiopoietin-1 (Ang1), Angiopoietin-2 (Ang2) and VEGF were measured by ELISA in 47 SSc patients and 27 healthy controls. Microvascular alterations were assessed by nailfold videocapillaroscopy (NVC). RESULTS Serum concentrations of Ang1 were significantly lower [mean (S.D.): 21516.04 (11,441.035) pg/ml], and Ang2 significantly increased [25,89.55 (934.225) pg/ml] in SSc as compared with the control group [Ang1: 28,457.08 (10,431.905) pg/ml; Ang2: 1556.23 (481.255) pg/ml, p < 0.01, respectively], whereas VEGF did not differ significantly. The ratios of Ang1/Ang2 and Ang1/VEGF were significantly lower in SSc patients (8.346 ± 4.523 and 95.17 ± 75.0, respectively) than in healthy subjects (17.612 ± 6.731 p < 0.000001 and 183.11 ± 137.73; p = 0.004]. Formation of giant capillaries with vascular leakage and collapse was associated with significant increase in VEGF and concomitant Ang1 deficiency. Capillary loss was related to significant increase in VEGF with respect to those with preserved capillary number (395.12 ± 256.27 pg/mL vs. 254.80 ± 213.61 pg/mL) whereas elevated Ang2 levels induced more advanced capillary damage as indicated by the presence of the "Late" NVC pattern. CONCLUSIONS We found that serum levels of Ang1, Ang2 and VEGF are differentially expressed in SSc and altered Ang1/Ang2 profile might underlay the aberrant angiogenesis in SSc despite increase in VEGF. For the first time we identified that significant deficiency of Ang1 might be involved in early capillary enlargement, followed by collapse and lack of stable newly-formed vessels in VEGF-enriched environment, whereas Ang2 levels seem to increase later in disease progression and advanced microvascular damage ("Late" NVC pattern).
Collapse
Affiliation(s)
- Małgorzata Michalska-Jakubus
- Department of Dermatology, Venereology and Paediatric Dermatology, Medical University of Lublin, Lublin, Poland.
| | - Maurizio Cutolo
- Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Genoa, Italy.
| | - Vanessa Smith
- Faculty of Internal Medicine, Ghent University, Belgium.
| | - Dorota Krasowska
- Department of Dermatology, Venereology and Paediatric Dermatology, Medical University of Lublin, Lublin, Poland.
| |
Collapse
|
|
35
|
Asl ER, Rasmi Y, Khadem-Ansari MH, Seyed-Mohammadzad M, Rostamzadeh A, Ghaffari F, Mokarizadeh N. Increased levels of angiogenic factors in microvascular angina. Med Pharm Rep 2019; 92:31-35. [PMID: 30957084 PMCID: PMC6448487 DOI: 10.15386/cjmed-1101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 09/16/2018] [Accepted: 09/27/2018] [Indexed: 11/23/2022] Open
Abstract
Background Recent studies have suggested that angiogenic factors may affect vascular endothelial integrity. On the other hand, endothelial dysfunction is the main pathological mechanism in microvascular angina (MVA) or cardiac syndrome X. Therefore, we aimed to determine the levels of angiogenic factors in MVA patients. In addition, we investigated the effects of metoprolol, as a beta blocker agent, on the serum levels of these factors. Methods Thirty patients with MVA (17 female/13 male; mean age: 55.53±9.18 years) and twenty healthy controls (14 female/6 male; mean age: 51.40±9.16 years) were enrolled. The serum amounts of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and tyrosine kinase-2 receptor (Tie-2) were measured in healthy controls, MVA patients at baseline and after metoprolol therapy (25 mg for one month) by enzyme-linked immunosorbent assay. Results The levels of Ang-2 and Tie-2 were significantly higher in MVA patients at baseline in comparison with controls (Ang-2: 277.02±186.08 vs.164.46±49.83 ng/l, P=0.011; Tie-2: 28.97±18.85 vs. 14.90±4.05 ng/ml, P=0.002; respectively). But this difference in the Ang-1 levels was not significant (P=0.829). Additionally, the levels of angiogenic factors in MVA patients after metoprolol therapy were not significantly changed in comparison with the baseline status (P>0.05). Conclusion Our results considered a possible role for angiogenic factors in the pathophysiology of MVA, which need further investigation for elucidation. In addition, this study has not showed an effective role for metoprolol in changing the angiogenic factors levels as a therapeutic agent in MVA.
Collapse
Affiliation(s)
- Elmira Roshani Asl
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yousef Rasmi
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | | | | | - Alireza Rostamzadeh
- Department of Cardiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Fereshteh Ghaffari
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Narmin Mokarizadeh
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| |
Collapse
|
|
36
|
Ghanem HB, Elsheikh M, El-Benhawy SA, Shahba A. Adipocytokines, inflammatory, epigenetic instability & angiogenesis biomarkers in type 2 diabetic Egyptian women with breast cancer. Diabetes Metab Syndr 2019; 13:24-29. [PMID: 30641704 DOI: 10.1016/j.dsx.2018.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 08/09/2018] [Indexed: 01/02/2023]
Abstract
Obesity is the main determinant of type 2 diabetes. Some adipocytokines play important roles in diabetic complications. Lipid transport is an important aspect of lipid metabolism in cancer. Present study aimed to evaluate the effect of some adipocytokines, inflammatory, epigenetic instability & angiogenesis biomarkers in type 2 diabetic Egyptian women with breast cancer. Study Design was performed on eighty females divided into 20 healthy subjects (Group I), 20 patients with type 2 diabetes (Group II), 20 patients with breast cancer (Group III) & 20 patients with diabetes and breast cancer (Group IV). Demographic data & body mass index have been collected. Biochemical analysis included fasting & postprandial blood glucose, lipid profile, fatty acid-binding proteins-4 (FABP-4), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), 8-hydroxy-2'-deoxyguanosine (8-OHdG) & thioredoxin reductase (TrxR) activity. Results revealed significant increase in FABP-4, TNF-α, VEGF, 8-OHdG and significant decreased TrxR activity in diabetic patients with breast cancer in comparison with other groups. These changes were evident in breast cancer subjects than diabetic and healthy cases and in diabetic than healthy cases. Conclusion: This study confirmed the role of FABP-4 in pathogenesis of type 2 diabetes & breast cancer via enhancing angiogenesis, inflammatory and epigenetic instability biomarkers.
Collapse
Affiliation(s)
- Heba Bassiony Ghanem
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, El-Geesh Street, Tanta, Egypt.
| | - Mohammed Elsheikh
- General Surgery Department, Faculty of Medicine, Tanta University, El-Geesh Street, Tanta, Egypt
| | - Sanaa Ali El-Benhawy
- Radiation Sciences Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Abeer Shahba
- Internal Medicine Department, Faculty of Medicine, Tanta University, El-Geesh Street, Tanta, Egypt
| |
Collapse
|
|
37
|
Puddu A, Sanguineti R, Maggi D, Nicolò M, Traverso CE, Cordera R, Viviani GL. Advanced Glycation End-Products and Hyperglycemia Increase Angiopoietin-2 Production by Impairing Angiopoietin-1-Tie-2 System. J Diabetes Res 2019; 2019:6198495. [PMID: 31828164 PMCID: PMC6881581 DOI: 10.1155/2019/6198495] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 10/11/2019] [Accepted: 10/18/2019] [Indexed: 12/19/2022] Open
Abstract
The angiopoietin-Tie-2 system plays a crucial role in the maintenance of endothelial integrity. Hyperglycemia and advanced glycation end-products (AGEs) are involved in endothelial cell dysfunction responsible of the pathogenesis of microvascular complications of diabetes. Here, we investigated whether glycated serum (GS) or hyperglycemia (HG) affect the angiopoietin-Tie-2 system in the microvascular endothelial cells HMEC-1. We found that culture for 5 days in the presence of AGEs and HG (alone or in combination) decreased cell proliferation, increased reactive oxygen species (ROS) production, and reduced ratio between the oxidized and the reduced form of glutathione. Since angiopoietin-1 (Ang-1) signaling regulates angiopoietin-2 (Ang-2) expression through inactivation of the forkhead transcription factor FoxO1, we investigated intracellular signaling of Ang-1 and expression of Ang-2. HG and AGEs reduced phosphorylation of Akt and abrogated phosphorylation of FoxO1 induced by Ang-1 without affecting neither Tie-2 expression nor its activation. Furthermore, AGEs and/or HG induced nuclear translocation of FoxO1 and increased Ang-2 production. In conclusion, we demonstrated that both hyperglycemia and AGEs affect the angiopoietin-Tie-2 system by impairing Ang-1/Tie-2 signaling and by increasing Ang-2 expression. These results suggest that therapeutic strategies useful in preventing or delaying the onset of diabetic vascular complications should be aimed to preserve Ang-1 signaling.
Collapse
Affiliation(s)
- Alessandra Puddu
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
| | - Roberta Sanguineti
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
| | - Davide Maggi
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
| | - Massimo Nicolò
- Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Genova 16132, Italy
- Fondazione per la Macula Onlus, Genova 16132, Italy
| | - Carlo E. Traverso
- Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Genova 16132, Italy
| | - Renzo Cordera
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
| | - Giorgio L. Viviani
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
| |
Collapse
|
|
38
|
Tsai YC, Kuo PL, Hung WW, Wu LY, Wu PH, Chang WA, Kuo MC, Hsu YL. Angpt2 Induces Mesangial Cell Apoptosis through the MicroRNA-33-5p-SOCS5 Loop in Diabetic Nephropathy. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 13:543-555. [PMID: 30414568 PMCID: PMC6226567 DOI: 10.1016/j.omtn.2018.10.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 09/30/2018] [Accepted: 10/03/2018] [Indexed: 02/03/2023]
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Mesangial cell (MC) loss is correlated with worsening renal function in DN. Disturbance of angiopoietin (Angpt)/Tie ligand-receptor system causes inflammation and abnormal angiogenesis. This association between elevated circulating Angpt2 and poor renal outcome has been in DN patients. However, the pathogenic role of Angpt2 in the MCs remains unknown. We found serum Angpt2 levels were elevated in type 2 diabetes mellitus (DM) patients and db/db mice, which correlated with albuminuria. Angpt2 synergistically induced MC apoptosis under high glucose (HG), and miR-33-5p regulated Angpt2-inducing MC apoptosis treated with HG. Loss of miR-33-5p increased suppressor of cytokine signaling 5 (SOCS5), leading to the inhibition of Janus kinase 1 and signal transducer and activator of transcription 3 signaling transduction. Elevated expression of SOCS5 was found in the MCs in kidney sections of both db/db mice and type 2 DM patients. Decreased miR-33-5p levels were found in the urine of db/db mice and type 2 DM patients, and miR-33-55p levels negatively correlated with albuminuria. Angpt2 leads to MC apoptosis via the miR-33-5p-SOCS5 loop in DN. miR-33-5p is predictive of kidney injury in DN. These findings may provide future applications in predicting renal dysfunction and the therapeutic potential of DN.
Collapse
Affiliation(s)
- Yi-Chun Tsai
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Po-Lin Kuo
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wei-Wen Hung
- Division of Endocrinology and Metabolism, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ling-Yu Wu
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ping-Hsun Wu
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Wei-An Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Mei-Chuan Kuo
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Ya-Ling Hsu
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
| |
Collapse
|
|
39
|
|
|
40
|
Ye X, Beckett T, Bagher P, Garland CJ, Dora KA. VEGF-A inhibits agonist-mediated Ca 2+ responses and activation of IK Ca channels in mouse resistance artery endothelial cells. J Physiol 2018; 596:3553-3566. [PMID: 29862503 DOI: 10.1113/jp275793] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 05/15/2018] [Indexed: 01/06/2023] Open
Abstract
KEY POINTS Prolonged exposure to vascular endothelial growth factor A (VEGF-A) inhibits agonist-mediated endothelial cell Ca2+ release and subsequent activation of intermediate conductance Ca2+ -activated K+ (IKCa ) channels, which underpins vasodilatation as a result of endothelium-dependent hyperpolarization (EDH) in mouse resistance arteries. Signalling via mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) downstream of VEGF-A was required to attenuate endothelial cell Ca2+ responses and the EDH-vasodilatation mediated by IKCa activation. VEGF-A exposure did not modify vasodilatation as a result of the direct activation of IKCa channels, nor the pattern of expression of inositol 1,4,5-trisphosphate receptor 1 within endothelial cells of resistance arteries. These results indicate a novel role for VEGF-A in resistance arteries and suggest a new avenue for investigation into the role of VEGF-A in cardiovascular diseases. ABSTRACT Vascular endothelial growth factor A (VEGF-A) is a potent permeability and angiogenic factor that is also associated with the remodelling of the microvasculature. Elevated VEGF-A levels are linked to a significant increase in the risk of cardiovascular dysfunction, although it is unclear how VEGF-A has a detrimental, disease-related effect. Small resistance arteries are central determinants of peripheral resistance and endothelium-dependent hyperpolarization (EDH) is the predominant mechanism by which these arteries vasodilate. Using isolated, pressurized resistance arteries, we demonstrate that VEGF-A acts via VEGF receptor-2 (R2) to inhibit both endothelial cell (EC) Ca2+ release and the associated EDH vasodilatation mediated by intermediate conductance Ca2+ -activated K+ (IKCa ) channels. Importantly, VEGF-A had no direct effect against IKCa channels. Instead, the inhibition was crucially reliant on the downstream activation of the mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 (MEK1/2). The distribution of EC inositol 1,4,5-trisphosphate (IP3 ) receptor-1 (R1) was not affected by exposure to VEGF-A and we propose an inhibition of IP3 R1 through the MEK pathway, probably via ERK1/2. Inhibition of EC Ca2+ via VEGFR2 has profound implications for EDH-mediated dilatation of resistance arteries and could provide a mechanism by which elevated VEGF-A contributes towards cardiovascular dysfunction.
Collapse
Affiliation(s)
- Xi Ye
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
| | - Taylor Beckett
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.,School of Biomedical Sciences, University of Queensland, Brisbane, Australia
| | - Pooneh Bagher
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.,Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA
| | | | - Kim A Dora
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
| |
Collapse
|
|
41
|
McCarthy CP, Ibrahim NE, van Kimmenade RRJ, Gaggin HK, Simon ML, Gandhi P, Kelly N, Motiwala SR, Mukai R, Magaret CA, Barnes G, Rhyne RF, Garasic JM, Januzzi JL. A clinical and proteomics approach to predict the presence of obstructive peripheral arterial disease: From the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) Study. Clin Cardiol 2018; 41:903-909. [PMID: 29876944 DOI: 10.1002/clc.22939] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 02/20/2018] [Accepted: 03/04/2018] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Peripheral arterial disease (PAD) is a global health problem that is frequently underdiagnosed and undertreated. Noninvasive tools to predict the presence and severity of PAD have limitations including inaccuracy, cost, or need for intravenous contrast and ionizing radiation. HYPOTHESIS A clinical/biomarker score may offer an attractive alternative diagnostic method for PAD. METHODS In a prospective cohort of 354 patients referred for diagnostic peripheral and/or coronary angiography, predictors of ≥50% stenosis in ≥1 peripheral vessel (carotid/subclavian, renal, or lower extremity arteries) were identified from >50 clinical variables and 109 biomarkers. Machine learning identified variables predictive of obstructive PAD; a score derived from the final model was developed. RESULTS The score consisted of 1 clinical variable (history of hypertension) and 6 biomarkers (midkine, kidney injury molecule-1, interleukin-23, follicle-stimulating hormone, angiopoietin-1, and eotaxin-1). The model had an in-sample area under the receiver operating characteristic curve of 0.85 for obstructive PAD and a cross-validated area under the curve of 0.84; higher scores were associated with greater severity of angiographic stenosis. At optimal cutoff, the score had 65% sensitivity, 88% specificity, 76% positive predictive value (PPV), and 81% negative predictive value (NPV) for obstructive PAD and performed consistently across vascular territories. Partitioning the score into 5 levels resulted in a PPV of 86% and NPV of 98% in the highest and lowest levels, respectively. Elevated score was associated with shorter time to revascularization during 4.3 years of follow-up. CONCLUSIONS A clinical/biomarker score demonstrates high accuracy for predicting the presence of PAD.
Collapse
Affiliation(s)
- Cian P McCarthy
- Department of Medicine, Massachusetts General Hospital, Boston
| | | | | | - Hanna K Gaggin
- Division of Cardiology, Massachusetts General Hospital, Boston.,Baim Institute for Clinical Research, Cardiometabolic Trials, Boston, Massachusetts
| | - Mandy L Simon
- Division of Cardiology, Massachusetts General Hospital, Boston
| | - Parul Gandhi
- Division of Cardiology, VA Connecticut Healthcare System and Yale University, New Haven, Connecticut
| | - Noreen Kelly
- Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Shweta R Motiwala
- Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Renata Mukai
- Division of Cardiology, Massachusetts General Hospital, Boston
| | | | | | | | | | - James L Januzzi
- Division of Cardiology, Massachusetts General Hospital, Boston.,Baim Institute for Clinical Research, Cardiometabolic Trials, Boston, Massachusetts
| |
Collapse
|
|
42
|
Siddiqui K, Joy SS, Nawaz SS, Al Otaibi MT, Al-Rubeaan K. Angiopoietin-2 level as a tool for cardiovascular risk stratification in hypertensive type 2 diabetic subjects. Postgrad Med 2018; 130:402-408. [DOI: 10.1080/00325481.2018.1469370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Khalid Siddiqui
- Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Salini Scaria Joy
- Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Shaik Sarfaraz Nawaz
- Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | | | - Khalid Al-Rubeaan
- Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- University Diabetes Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| |
Collapse
|
|
43
|
Tsai YC, Lee CS, Chiu YW, Lee JJ, Lee SC, Hsu YL, Kuo MC. Angiopoietin-2, Renal Deterioration, Major Adverse Cardiovascular Events and All-Cause Mortality in Patients with Diabetic Nephropathy. Kidney Blood Press Res 2018; 43:545-554. [PMID: 29642068 DOI: 10.1159/000488826] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 03/28/2018] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Diabetic nephropathy is the leading cause of end-stage renal disease and accounts for 30∼40% of patients requiring maintenance dialysis, thereby increasing the burden on health insurance programs. Diabetic nephropathy is also the strongest predictor of cardiovascular morbidity and mortality. The aim of this study was to examine whether angiopoietin-2 (Angpt2), a modulator of endothelial function, affects the clinical outcomes of diabetic patients. METHODS This study enrolled 236 patients with diabetes mellitus with estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m2 from January 2006 to December 2011, who were followed until June 2017. Clinical outcomes included renal outcomes (commencing dialysis and rapid decline in renal function (eGFR decline > 3 ml/min per 1.73 m2/year)), major adverse cardiovascular events (MACEs), and all-cause mortality. RESULTS Over a mean follow-up period of 3.9±2.7 years, 135 (57.2%) patients commenced dialysis, 106 (44.9%) had rapid decline in renal function, and 50 (21.2%) had MACEs or died from all-causes. Log-formed Angpt2 was significantly associated with increased risks of commencing dialysis (HR: 3.91, 95% CI: 1.56-9.76), rapid renal function decline (OR: 6.81, 95% CI: 1.06-43.88), and MACEs or all-cause mortality (HR: 6.34, 95% CI: 1.18-33.97) in the adjusted analysis. Patients in the highest quartile had hazard ratios of 2.90 and 3.11 for commencing dialysis and rapid renal function decline, respectively, compared to those in the lowest quartile after adjustments. Similar significant dose-response results were found in composite outcomes of either MACEs or all-cause mortality. CONCLUSION Angpt2 is an independent predictor of adverse clinical outcomes in diabetic patients. Further studies are needed to identify the pathogenic role of Angpt2 in renal deterioration and cardiovascular complications of diabetes mellitus.
Collapse
Affiliation(s)
- Yi-Chun Tsai
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Renal Care, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chee-Siong Lee
- Division of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Division of Cardiology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Wen Chiu
- Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Renal Care, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jia-Jung Lee
- Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Renal Care, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Su-Chu Lee
- Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ya-Ling Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mei-Chuan Kuo
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Renal Care, Kaohsiung Medical University, Kaohsiung, Taiwan
| |
Collapse
|
|
44
|
Loganathan K, Salem Said E, Winterrowd E, Orebrand M, He L, Vanlandewijck M, Betsholtz C, Quaggin SE, Jeansson M. Angiopoietin-1 deficiency increases renal capillary rarefaction and tubulointerstitial fibrosis in mice. PLoS One 2018; 13:e0189433. [PMID: 29293543 PMCID: PMC5749705 DOI: 10.1371/journal.pone.0189433] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 11/24/2017] [Indexed: 01/06/2023] Open
Abstract
Presence of tubulointerstitial fibrosis is predictive of progressive decline in kidney function, independent of its underlying cause. Injury to the renal microvasculature is a major factor in the progression of fibrosis and identification of factors that regulate endothelium in fibrosis is desirable as they might be candidate targets for treatment of kidney diseases. The current study investigates how loss of Angipoietin-1 (Angpt1), a ligand for endothelial tyrosine-kinase receptor Tek (also called Tie2), affects tubulointerstitial fibrosis and renal microvasculature. Inducible Angpt1 knockout mice were subjected to unilateral ureteral obstruction (UUO) to induce fibrosis, and kidneys were collected at different time points up to 10 days after obstruction. Staining for aSMA showed that Angpt1 deficient kidneys had significantly more fibrosis compared to wildtype mice 3, 6, and 10 days after UUO. Further investigation 3 days after UUO showed a significant increase of Col1a1 and vimentin in Angpt1 deficient mice, as well as increased gene expression of Tgfb1, Col1a1, Fn1, and CD44. Kidney injury molecule 1 (Kim1/Havcr1) was significantly more increased in Angpt1 deficient mice 1 and 3 days after UUO, suggesting a more severe injury early in the fibrotic process in Angpt1 deficient mice. Staining for endomucin showed that capillary rarefaction was evident 3 days after UUO and Angpt1 deficient mice had significantly less capillaries 6 and 10 days after UUO compared to UUO kidneys in wildtype mice. RNA sequencing revealed downregulation of several markers for endothelial cells 3 days after UUO, and that Angpt1 deficient mice had a further downregulation of Emcn, Plvap, Pecam1, Erg, and Tek. Our results suggest that loss of Angpt1 is central in capillary rarefaction and fibrogenesis and propose that manipulations to maintain Angpt1 levels may slow down fibrosis progression.
Collapse
Affiliation(s)
| | - Ebtisam Salem Said
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Emily Winterrowd
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Martina Orebrand
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Liqun He
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China
| | - Michael Vanlandewijck
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden
| | - Christer Betsholtz
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden
| | - Susan E. Quaggin
- Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, United States of America
- Division of Nephrology and Hypertension, Northwestern University, Chicago, IL, United States of America
| | - Marie Jeansson
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- * E-mail:
| |
Collapse
|
|
45
|
Zafar MI, Mills K, Ye X, Blakely B, Min J, Kong W, Zhang N, Gou L, Regmi A, Hu SQ, Zheng J, Chen LL. Association between the expression of vascular endothelial growth factors and metabolic syndrome or its components: a systematic review and meta-analysis. Diabetol Metab Syndr 2018; 10:62. [PMID: 30087698 PMCID: PMC6076391 DOI: 10.1186/s13098-018-0363-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 07/30/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Several studies have linked vascular endothelial growth factors (VEGFs) with metabolic syndrome or its components. However, there has been no systematic appraisal of the findings of these studies to date. The current systematic review and meta-analysis was conducted to explore this association. METHODS PubMed, EMBASE, the Cochrane library, and clinical trials registries were used to retrieve peer-reviewed clinical studies that had evaluated the association of VEGFs with metabolic syndrome or its components without applying language and date restrictions. The final search was performed on 29 September 2017. RESULTS We included 32 studies in this systematic review and meta-analysis, of which 16 studies (19 study arms) were included in the meta-analysis and remaining studies were qualitatively assessed. Overall, VEGF-A, VEGF-B and VEGF-C were strongly associated with metabolic syndrome or its components. The components of metabolic syndrome varied in their association. Obesity was not correlated with increased VEGF-A expression (p = 0.12), whereas VEGF-B and VEGF-C expression was significantly higher in those with obesity. In contrast, hyperglycemia in type 1 diabetes was strongly associated with increased VEGF-A levels (p < 0.00001), as was type 2 diabetes (p = 0.0006). The studies included in the qualitative analysis similarly showed an increase in VEGF family expression in people with metabolic syndrome, and with its components. CONCLUSION The increased concentrations of vascular endothelial growth factors are variably associated with metabolic syndrome or its components. Each VEGF protein has a unique set of associations with the disease state.
Collapse
Affiliation(s)
- Mohammad Ishraq Zafar
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Kerry Mills
- Health Research Institute, University of Canberra, Canberra, Australia
| | - Xiaofeng Ye
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Brette Blakely
- Centre for Healthcare Resilience and Implementation Science (CHRIS), Australian Institute of Health Innovation, Macquarie University, Sydney, NSW Australia
| | - Jie Min
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Wen Kong
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Nan Zhang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Luoning Gou
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Anita Regmi
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Sheng Qing Hu
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Juan Zheng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Lu-Lu Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| |
Collapse
|
|
46
|
Circulating Angiogenic Growth Factors in Diabetes Patients with Peripheral Arterial Disease and Exertional Leg Pain in Ghana. Int J Vasc Med 2017; 2017:2390174. [PMID: 29445546 PMCID: PMC5763056 DOI: 10.1155/2017/2390174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 11/27/2017] [Accepted: 11/29/2017] [Indexed: 11/29/2022] Open
Abstract
Objective Peripheral arterial disease (PAD) is a common complication of diabetes, associated with impairment in angiogenesis. Angiogenesis is regulated by angiogenic growth factors such as angiopoietin 1 (Ang-1), Ang-2, and vascular endothelial growth factor (VEGF). We studied the association between angiogenic growth factors versus PAD and exertional leg symptoms in diabetes patients in Ghana. Method In this cross-sectional study, ankle-brachial index was measured with oscillometrically and exertional leg symptoms were screened with Edinburgh claudication questionnaire in 140 diabetes patients and 110 nondiabetes individuals. Circulating levels of Ang-1, Ang-2, and VEGF were measured with immunosorbent assay. Results The prevalence of PAD and exertional leg pain was 16.8% and 24.8%, respectively. Compared to non-PAD participants, PAD patients had higher VEGF levels [85.8 (37.5–154.5) versus 57.7 (16.6–161.1) p = 0.032] and lower Ang-1 levels [31.3 (24.8–42.6) versus 40.9 (28.2–62.1), p = 0.017]. In multivariable logistic regression, patients with exertional leg pain had increased the odds of plasma Ang-2 levels [OR (95% CI): 2.08 (1.08–6.41), p = 0.036]. Conclusion Diabetes patients with PAD and exertional leg pain have imbalance in angiogenic growth factors, indicating impaired angiogenesis. In patients with exertional leg pains, Ang-2 may be an important biomarker.
Collapse
|
|
47
|
Rani J, Mittal I, Pramanik A, Singh N, Dube N, Sharma S, Puniya BL, Raghunandanan MV, Mobeen A, Ramachandran S. T2DiACoD: A Gene Atlas of Type 2 Diabetes Mellitus Associated Complex Disorders. Sci Rep 2017; 7:6892. [PMID: 28761062 PMCID: PMC5537262 DOI: 10.1038/s41598-017-07238-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 06/28/2017] [Indexed: 12/11/2022] Open
Abstract
We performed integrative analysis of genes associated with type 2 Diabetes Mellitus (T2DM) associated complications by automated text mining with manual curation and also gene expression analysis from Gene Expression Omnibus. They were analysed for pathogenic or protective role, trends, interaction with risk factors, Gene Ontology enrichment and tissue wise differential expression. The database T2DiACoD houses 650 genes, and 34 microRNAs associated with T2DM complications. Seven genes AGER, TNFRSF11B, CRK, PON1, ADIPOQ, CRP and NOS3 are associated with all 5 complications. Several genes are studied in multiple years in all complications with high proportion in cardiovascular (75.8%) and atherosclerosis (51.3%). T2DM Patients' skeletal muscle tissues showed high fold change in differentially expressed genes. Among the differentially expressed genes, VEGFA is associated with several complications of T2DM. A few genes ACE2, ADCYAP1, HDAC4, NCF1, NFE2L2, OSM, SMAD1, TGFB1, BDNF, SYVN1, TXNIP, CD36, CYP2J2, NLRP3 with details of protective role are catalogued. Obesity is clearly a dominant risk factor interacting with the genes of T2DM complications followed by inflammation, diet and stress to variable extents. This information emerging from the integrative approach used in this work could benefit further therapeutic approaches. The T2DiACoD is available at www.http://t2diacod.igib.res.in/ .
Collapse
Affiliation(s)
- Jyoti Rani
- G N Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), Room No. 130, Mathura Road, New Delhi, 110025, India
| | - Inna Mittal
- G N Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), Room No. 130, Mathura Road, New Delhi, 110025, India
| | - Atreyi Pramanik
- G N Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), Room No. 130, Mathura Road, New Delhi, 110025, India
| | - Namita Singh
- G N Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), Room No. 130, Mathura Road, New Delhi, 110025, India
| | - Namita Dube
- G N Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), Room No. 130, Mathura Road, New Delhi, 110025, India
| | - Smriti Sharma
- G N Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), Room No. 130, Mathura Road, New Delhi, 110025, India
| | - Bhanwar Lal Puniya
- G N Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), Room No. 130, Mathura Road, New Delhi, 110025, India
| | - Muthukurussi Varieth Raghunandanan
- G N Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), Room No. 130, Mathura Road, New Delhi, 110025, India
| | - Ahmed Mobeen
- G N Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), Room No. 130, Mathura Road, New Delhi, 110025, India
- Academy of Scientific and Innovative Research, CSIR-IGIB South Campus, New Delhi, 110025, India
| | - Srinivasan Ramachandran
- G N Ramachandran Knowledge of Centre, Council of Scientific and Industrial Research - Institute of Genomics and Integrative Biology (CSIR-IGIB), Room No. 130, Mathura Road, New Delhi, 110025, India.
- Academy of Scientific and Innovative Research, CSIR-IGIB South Campus, New Delhi, 110025, India.
| |
Collapse
|
|
48
|
Treweeke A, Hall J, Lambie S, Leslie SJ, Megson IL, MacRury SM. Preliminary study of hypoxia-related cardiovascular mediator-markers in patients with end-stage renal disease with and without diabetes and the effects of haemodialysis. PLoS One 2017; 12:e0178171. [PMID: 28542479 PMCID: PMC5441650 DOI: 10.1371/journal.pone.0178171] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 05/08/2017] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Evidence points to activation of pro-inflammatory and pro-thrombotic stimuli during the haemodialysis process in end-stage renal disease (ESRD) with potential to predispose to cardiovascular events. Diabetes is associated with a higher incidence of cardiovascular disease in haemodialysis patients. We tested the hypothesis that a range of mediators and markers that modulate cardiovascular risk are elevated in haemodialysis patients with diabetes compared to those without. METHODS Men and women with diabetes (n = 6) and without diabetes (n = 6) aged 18-90 years receiving haemodialysis were recruited. Blood samples were collected and analysed pre- and post-haemodialysis sessions for (platelet-monocyte conjugates (PMC), oxidised LDL (Ox-LDL), endothelin 1 (ET-1) and vascular endothelial growth factor (VEGF-A). RESULTS PMC levels significantly increased after haemodialysis in both groups (diabetes p = 0.047; non-diabetes p = 0.005). Baseline VEGF-A was significantly higher in people with diabetes (p = 0.009) and post-dialysis levels were significantly reduced in both groups (P = 0.002). Ox-LDL and CRP concentrations were not significantly different between groups nor affected in either group post-dialysis. Similarly, ET-1 concentrations were comparable in all patients at baseline, with no change post-dialysis in either group. CONCLUSIONS In this pilot study, we have confirmed that circulating PMCs are increased following dialysis irrespective of diabetes status. This is likely to be a mechanistic process and offers a potential explanation for high rates of vascular events associated with haemodialysis. The higher VEGF-A concentrations between patients with and without diabetes is a previously unreported finding in diabetic ESRD. Further research is merited to establish whether VEGF-A is a marker or mediator (or both) of cardiovascular risk in haemodialysis.
Collapse
Affiliation(s)
- A. Treweeke
- Division of Health Research, University of the Highlands and Islands, Inverness, Scotland
| | - J. Hall
- Division of Health Research, University of the Highlands and Islands, Inverness, Scotland
| | - S. Lambie
- Department of Medicine, Raigmore Hospital, Inverness, Scotland
| | - S. J. Leslie
- Division of Health Research, University of the Highlands and Islands, Inverness, Scotland
- Department of Medicine, Raigmore Hospital, Inverness, Scotland
| | - I. L. Megson
- Division of Health Research, University of the Highlands and Islands, Inverness, Scotland
| | - S. M. MacRury
- Division of Health Research, University of the Highlands and Islands, Inverness, Scotland
- Department of Medicine, Raigmore Hospital, Inverness, Scotland
| |
Collapse
|
|
49
|
Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov 2017; 16:635-661. [PMID: 28529319 DOI: 10.1038/nrd.2016.278] [Citation(s) in RCA: 409] [Impact Index Per Article: 51.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The endothelial angiopoietin (ANG)-TIE growth factor receptor pathway regulates vascular permeability and pathological vascular remodelling during inflammation, tumour angiogenesis and metastasis. Drugs that target the ANG-TIE pathway are in clinical development for oncological and ophthalmological applications. The aim is to complement current vascular endothelial growth factor (VEGF)-based anti-angiogenic therapies in cancer, wet age-related macular degeneration and macular oedema. The unique function of the ANG-TIE pathway in vascular stabilization also renders this pathway an attractive target in sepsis, organ transplantation, atherosclerosis and vascular complications of diabetes. This Review covers key aspects of the function of the ANG-TIE pathway in vascular disease and describes the recent development of novel therapeutics that target this pathway.
Collapse
Affiliation(s)
- Pipsa Saharinen
- Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, FI-00014 Helsinki, Finland
| | - Lauri Eklund
- Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, Aapistie 5A, University of Oulu, 90220 Oulu, Finland
| | - Kari Alitalo
- Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, FI-00014 Helsinki, Finland
| |
Collapse
|
|
50
|
Narayanan S, Loganathan G, Dhanasekaran M, Tucker W, Patel A, Subhashree V, Mokshagundam S, Hughes MG, Williams SK, Balamurugan AN. Intra-islet endothelial cell and β-cell crosstalk: Implication for islet cell transplantation. World J Transplant 2017; 7:117-128. [PMID: 28507914 PMCID: PMC5409911 DOI: 10.5500/wjt.v7.i2.117] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 02/28/2017] [Accepted: 03/24/2017] [Indexed: 02/05/2023] Open
Abstract
The intra-islet microvasculature is a critical interface between the blood and islet endocrine cells governing a number of cellular and pathophysiological processes associated with the pancreatic tissue. A growing body of evidence indicates a strong functional and physical interdependency of β-cells with endothelial cells (ECs), the building blocks of islet microvasculature. Intra-islet ECs, actively regulate vascular permeability and appear to play a role in fine-tuning blood glucose sensing and regulation. These cells also tend to behave as “guardians”, controlling the expression and movement of a number of important immune mediators, thereby strongly contributing to the physiology of islets. This review will focus on the molecular signalling and crosstalk between the intra-islet ECs and β-cells and how their relationship can be a potential target for intervention strategies in islet pathology and islet transplantation.
Collapse
|