Relationship between the Soluble F11 Receptor and Annexin A5 in African Americans Patients with Type-2 Diabetes Mellitus (original) (raw)
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Diabetologia, 2017
Microvascular complications in the heart and kidney are strongly associated with an overall rise in inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory molecule that limits and resolves inflammation. In this study, we have used a bedside to bench approach to investigate: (1) ANXA1 levels in individuals with type 1 diabetes; (2) the role of endogenous ANXA1 in nephropathy and cardiomyopathy in experimental type 1 diabetes; and (3) whether treatment with human recombinant ANXA1 attenuates nephropathy and cardiomyopathy in a murine model of type 1 diabetes. ANXA1 was measured in plasma from individuals with type 1 diabetes with or without nephropathy and healthy donors. Experimental type 1 diabetes was induced in mice by injection of streptozotocin (STZ; 45 mg/kg i.v. per day for 5 consecutive days) in C57BL/6 or Anxa1 (-/-) mice. Diabetic mice were treated with human recombinant (hr)ANXA1 (1 μg, 100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.) or vehicle (100 μl...
Annexin-A1: Therapeutic Potential in Microvascular Disease
Frontiers in Immunology
Annexin-A1 (ANXA1) was first discovered in the early 1980's as a protein, which mediates (some of the) anti-inflammatory effects of glucocorticoids. Subsequently, the role of ANXA1 in inflammation has been extensively studied. The biology of ANXA1 is complex and it has many different roles in both health and disease. Its effects as a potent endogenous anti-inflammatory mediator are well-described in both acute and chronic inflammation and its role in activating the pro-resolution phase receptor, FPR2, has been described and is now being exploited for therapeutic benefit. In the present mini review, we will endeavor to give an overview of ANXA1 biology in relation to inflammation and functions that mediate pro-resolution that are independent of glucocorticoid induction. We will focus on the role of ANXA1 in diseases with a large inflammatory component focusing on diabetes and microvascular disease. Finally, we will explore the possibility of exploiting ANXA1 as a novel therapeutic target in diabetes and the treatment of microvascular disease.
The role of Annexin-A1 in the pathophysiology of diabetes
2018
2.3. Experimental plan and groups…………………………….. 80 2.3.1. The effect of endogenous ANXA1 on STZ-induced diabetes mellitus 2.3.2. The effect of treatment with hrANXA1 on STZ-induced diabetes mellitus. 2.3.3. Effect of late treatment with hrANXA1 (weeks 8-13) on STZ-induced diabetes mellitus. 2.4. Results………………………………………………………………… 83 2.4.1. Quantification of plasma ANXA1 and C-reactive protein (CRP) levels in patients with type-1 diabetes 2.4.2. Correlation of BMI and CRP with AXNA1 in patients with type-1 diabetes………………………………………………………………………………… Gareth S. D. Purvis 11 2.4.3. Protein levels of ANXA1 in a murine model of STZ-induced type-1 diabetes mellitus. 2.4.4. The effect of endogenous ANXA1 on OGTT in a murine model of STZinduced type-1 diabetes mellitus. 2.4.5. The effect of endogenous ANXA1 on renal dysfunction in a murine model of STZ-induced type-1 diabetes mellitus. 2.4.6. The effect of endogenous ANXA1 on tubular function in a murine model of STZ-induced type-1 diabetes mellitus. 2.4.7. The effect of endogenous ANXA1 on glomerular hypertrophy in a murine model of STZ-induced type-1 diabetes mellitus. 2.4.8. The effect of endogenous ANXA1 on renal fibrosis in a model of STZinduced type-1 diabetes mellitus. 2.4.9. The effect of endogenous ANXA1 on cardiac dysfunction in a murine model of STZ-induced type-1 diabetes mellitus. 2.4.10. Effect of endogenous ANXA1 on cardiac hypertrophy in a murine model of STZ-induced type-1 diabetes mellitus. 2.4.11. Effect of endogenous ANXA1 on phosphorylation of p-38, JNK and ERK1/2 in kidneys from mice subjected to STZ-induced type-1 diabetes mellitus 2.4.12. Effect of endogenous ANXA1 on phosphorylation of Akt in kidneys from mice subjected to STZ-induced type-1 diabetes mellitus 2.4.13. The effect of endogenous ANXA1 on phosphorylation of p-38, JNK and ERK1/2 in kidneys from mice subjected to STZ-induced type-1 diabetes mellitus. 2.4.14. The effect of endogenous ANXA1 on phosphorylation of Akt in hearts from mice subjected to STZ-induced type-1 diabetes mellitus. 2.4.15. The effect of administration of hrANXA1 on non-fasted blood glucose, serum insulin and OGTT in mice subjected to STZ-induced type-1 diabetes mellitus. 2.4.16. The effect of administration of hrANXA1 on renal dysfunction in mice subjected to STZ-induced type-1 diabetes mellitus. 2.4.17. The effect of administration of hrANXA1 on the cardiac dysfunction in WT-mice subjected to STZ-induced type-1 diabetes mellitus. Gareth S. D. Purvis 12 2.4.18. The effect of late administration with hrANXA1 on non-fasted blood glucose, serum insulin and OGTT subjected to STZ-induced type-1 diabetes mellitus. 2.4.19. The effect of late treatment with hrANXA1 on renal dysfunction in mice subjected to STZ-induced type-1 diabetes mellitus. 2.4.20. The effect of late treatment with hrANXA1 on cardiac dysfunction in mice subjected to STZ-induced type-1 diabetes mellitus. 2.4.21. The effect of late treatment with hrANXA1 on the phosphorylation of p-38, JNK and ERK1/2 in kidneys from mice subjected to STZ-induced type-1 diabetes mellitus 2.4.22. The effect of late treatment with hrANXA1 on the phosphorylation of Akt in kidneys from mice subjected to STZ-induced type-1 diabetes mellitus. 2.5. Discussion…………………………………………………………… 134 Chapter III: Assessing the role of annexin-A1 in type-2 diabetes 3.1. Introduction………………………………………………………… 145 3.1.1. Specific aims 3.1.2. Methods and Materials………………………………………… 148 3.1.3. Use of human subjects-ethical statement 3.1.4. Use of animals-ethical statement 3.1.5. Sandwich ELISA for ANXA1 3.1.6. HFD induction of type-2 diabetes 3.1.7. Drug administration 3.1.8. Oral glucose tolerance test 3.1.9. Assessment of renal function 3.1.10. Organ and blood collection 3.1.11. Western blot analysis 3.1.12. Histological analysis 3.1.13. Statistical analysis Gareth S. D. Purvis 13 3.2. Experimental plan and groups……………………………. 153 3.2.1. The effect of treatment with hrANXA1 and endogenous ANXA1 in a model of HFD-induced insulin resistance. 3.3. Results………………………………………………………………. 154 3.3.1. ANXA1 levels are elevated in patients with type-2 diabetes, independent of having diabetic nephropathy. 3.3.2. ANXA1 levels are strong correlated with increasing sera lipids but not systemic inflammation. 3.3.3. The effect of treatment with hrANXA1 and the role of endogenous ANXA1 on body weights in a murine model of diet-induced insulin resistance. 3.3.4. The effect of treatment with hrANXA1 and the role of endogenous ANXA1 on Oil RedO staining in a murine model of diet-induced insulin resistance. 3.3.5. The effect of hrANXA1 administration and the role of endogenous ANXA1 on triglyceride and cholesterol level in the liver of a murine model of dietinduced insulin resistance. 3.3.6. The effect of hrANXA1 administration and the role of endogenous ANXA1 on triglyceride and cholesterol level in serum in a model of diet-induced insulin resistance. 3.3.7. The effect of hrANXA1 administration and the role of endogenous ANXA1 on baseline diabetic parameters in a model of diet-induced insulin resistance. 3.3.8. The effect of treatment with hrANXA1 and role of endogenous ANXA1 on insulin signalling pathways, in the liver, in a murine model of diet-induced insulin resistance. 3.3.9. The effect of hrANXA1 administration and role of endogenous ANXA1 on insulin signalling pathways, in skeletal muscle, in a murine model of dietinduced insulin resistance. 3.3.10. The effect of hrANXA1 administration and role of endogenous ANXA1 on renal dysfunction in a model of diet-induced insulin resistance. 3.3.11. The effect of hrANXA1 administration and role of endogenous ANXA1 on eNOS signalling in the kidney in a model of diet-induced insulin resistance. Gareth S. D. Purvis 14 3.3.12. The effect of hrANXA1 administration and role of endogenous ANXA1 on RhoA and MYPT1 signalling, in skeletal muscle, in a murine model of dietinduced insulin resistance. 3.3.13. The effect of hrANXA1 administration and role of endogenous ANXA1 on RhoA and MYPT1 signalling, in the liver, in a murine model of diet-induced insulin resistance. 3.3.14. the effect of hrANXA1 administration and role of endogenous ANXA1 on RhoA and MYPT1 signalling in the kidney in a murine model of diet-induced insulin resistance. 3.4. Discussion…………………………………………………………… 191 Chapter IV: Annexin-A1 linking peripheral inflammation and the BBB 4.1. Introduction……………………………………………….. 202 4.1.1. Specific aims 4.1.2. Methods and materials………………………………. 205 4.1.3. Use of animals-ethical statement 4.1.4. HFD induction of type-2 diabetes 4.1.5. Drug administration 4.1.6. T-cells isolation and expansion 4.1.7. T-cell migration in static condition 4.1.8. Membrane and intracellular FACS staining 4.1.9. Statistical analysis 4.2. Results……………………………………………………….. 208 4.2.1. The effect of hrANXA1 administration and the role of endogenous ANXA1 on BBB permeability in mice fed a HFD. 4.2.2. The role of endogenous ANXA1 on specific CD4 + lymphocyte populations from mice fed a HFD. Gareth S. D. Purvis 15 4.2.3. The role of endogenous ANXA1 on the ratio of CD4 + FoxP3 + to CD4 + RORγt + lymphocytes from mice fed a HFD. 4.2.4. The effect of treatment with hrANXA1 on specific CD4 + lymphocyte populations in mice fed a HFD. 4.2.5. The effect of treatment with hrANXA1 on the ratio of CD4 + FoxP3 + to CD4 + RORγt + lymphocytes from mice fed a HFD. 4.2.6. The effect of treatment with hrANXA1 on lymphocytes ability to adhere and transmigrate through an endothelial monolayer ex vivo. 4.2.7. The effect of treatment with hrANXA1 on specific CD4 + lymphocyte populations in mice fed a HFD that adhere to a brain endothelial monolayer ex vivo. 4.2.8. The effect of treatment with hrANXA1 on specific CD4 + lymphocyte populations in mice fed a HFD that transmigrate through a brain endothelial monolayer ex vivo. 4.2.9. The effect of treatment with hrANXA1 on the ratio of CD4 + FoxP3 + to CD4 + RORgt + lymphocytes from mice fed a HFD that adhere to and transmigrate through a brain endothelial monolayer ex vivo. 4.3. Discussion…………………………………………………. 226 Chapter V: General discussion 5.1 General discussion…………………………………………………. 235 5.2 Future perspectives………………………………………………... 244 Chapter II: The role of annexin-A1 in the microvascular complications of type-1 diabetes mellitus.
Annexin II Proteins: An Evaluation for Type 1 Diabetes Mellitus
Annexin II (AnxII) has diverse functions including anti-coagulant activity. The studies have suggested that antibodies against annexin II (aAnxIIs) might induce thrombosis by inhibiting plasmin generation in the course of autoimmune diseases. Type 1 diabetes mellitus (DM) is also an autoimmune condition that related with thrombotic complications, but there is no study regarding aAnxII/AnxII in this disease setting. The aim of this study was to evaluate the status of AnxII and aAnxII in patients with type 1 diabetes mellitus. One hundred twenty-five patients with type 1 DM and 92 healthy controls were enrolled to the study. Serum AnxII and aAnxIIs levels were quantified by enzyme-linked immunosorbent assays. The AnxII gene expression analysis was performed by Real Time PCR. As compared to controls, patients with type 1 DM had significantly higher serum AnxII levels. There were no significant differences in terms of aAnxII levels and AnxII gene expression between patients with type 1 DM and healthy controls. The present study shows that AnxII levels are increased in patients with type 1 DM. Further studies are required to determine the clinical importance of AnxII protein in type 1 diabetes.
Annexin V Expression and Anti-Annexin V Antibodies in Type 1 Diabetes
The Journal of Clinical Endocrinology & Metabolism, 2014
Background: Annexin V (AnxV) has potent anticoagulant properties and regulatory functions for apoptosis and inflammation. Antibodies against annexin V (anti-AnxVs) may inhibit AnxV functions, leading to thrombosis during autoimmune diseases. Type 1 diabetes is an autoimmune disease and related with an ongoing autoimmune inflammation and thrombotic complications. There is no study evaluating anti-AnxVs/AnxV in a disease setting. Objective: The aim of this study was to evaluate the status of AnxV and anti-AnxVs in patients with type 1 diabetes. Methods: One hundred twenty-one patients with type 1 diabetes and 92 healthy controls were included in this study. Serum levels of AnxV and anti-AnxVs and expression of the AnxV gene and its common polymorphism in Kozak sequence (Ϫ1CϾT) were studied. As a functional assay, the binding capacity of AnxV to platelets was evaluated. Results: As compared with controls, type 1 diabetic patients had significantly low serum AnxV levels and AnxV gene expression. The number of anti-AnxV positivity and their serum levels were significantly higher in type 1 diabetic patients than controls. AnxV binding to platelets were significantly decreased in the type 1 diabetic patients. The frequencies of the Ϫ1CϾT polymorphism of AnxV gene did not differ between groups. Conclusions: This study demonstrated the significant changes in AnxV levels and its function in type 1 diabetic patients. These results support the hypothesis that the defective AnxV system may have a role in ongoing autoimmune activity and the development of thrombotic complications in type 1 diabetes. Further studies are necessary to elucidate the clinical impact of anti-AnxVs and dysregulated AnxV function in type 1 diabetes.
2007
, on behalf of the ACTFAST investigators Objectives-Increasing evidence indicates that the Fas/Fas ligand interaction is involved in atherogenesis. We sought to analyze soluble Fas (sFas) and soluble Fas ligand (sFasL) concentrations in subjects at high cardiovascular risk and their modulation by atorvastatin treatment. Methods and Results-ACTFAST was a 12-week, prospective, multicenter, open-label trial which enrolled subjects (statin-free or statin-treated at baseline) with coronary heart disease (CHD), CHD-equivalent, or 10-year CHD risk Ͼ20%. Subjects with LDL-C between 100 to 220 mg/dL (2.6 to 5.7 mmol/L) and triglycerides Յ600 mg/dL (6.8 mmol/L) were assigned to a starting dose of atorvastatin (10 to 80 mg/d) based on LDL-C at screening. Of the 2117 subjects enrolled in ACTFAST, AIM sub-study included the 1078 statin-free patients. At study end, 85% of these subjects reached LDL-C target. Mean sFas levels were increased and sFasL were reduced in subjects at high cardiovascular risk compared with healthy subjects. Atorvastatin reduced sFas in the whole population as well as in patients with metabolic syndrome or diabetes. Minimal changes were observed in sFasL. Conclusions-sFas concentrations are increased and sFasL are decreased in subjects at high cardiovascular risk, suggesting that these proteins may be novel markers of vascular injury. Atorvastatin reduces sFas, indicating that short-term treatment with atorvastatin exhibits antiinflammatory effects in these subjects. (Arterioscler Thromb Vasc Biol. 2007;27:168-174.) Key Words: inflammation Ⅲ atorvastatin Ⅲ soluble Fas Ⅲ C-reactive protein Ⅲ statins C ardiovascular events arise from the disruption of atherosclerotic plaques that contain numerous inflammatory cells. 1 Inflammatory and resident cells (endothelial and vascular smooth muscle cells) release different proteins that can generate a chronic inflammatory response in the injured artery. Measurement of circulating markers of inflammation may provide some insight into this process. Proteins secreted by cells implicated in atherosclerotic lesions, including soluble Fas (sFas) and soluble Fas ligand (sFasL), circulate in small, but detectable, amounts. Soluble Fas is generated by alternative messenger RNA splicing capable of encoding a soluble Fas molecule lacking the transmembrane domain, 2 whereas sFasL is released in serum from membrane-bound FasL processed by a metalloproteinase. 3 It has been demonstrated that Fas and FasL are expressed in atherosclerotic lesions and the Fas/Fas ligand system is related to the apoptotic and inflammatory responses present in atherosclerotic plaques. 4-5 Fas and its ligand are typical members of the tumor necrosis factor (TNF) receptor superfamily. Similar to other members of this family, FasL induces apoptosis or programmed cell death when bound to its receptor Fas. 6 However, depending on the conditions, Fas/FasL interactions may be related to augmentation of proliferation and inflammatory response. 7 In this sense, signals initiated by regulated Fas-associated death domain protein overexpression in the carotid artery induce expression of monocyte-chemoattractant protein-1 and interleukin (IL)-8, and cause massive migration of macrophages in vivo, 8 indicating that Fas and Fas ligand act also as proinflammatory proteins.
Enhanced neutrophil expression of annexin-1 in coronary artery disease
Metabolism, 2010
Background: The systemic inflammatory activity in patients with stable coronary artery disease (CAD) is associated with a dysregulated cortisol response. Moreover, an aberrant activation status of neutrophils in CAD has been discussed; and the question of glucocorticoid resistance has been raised. The antiinflammatory actions of glucocorticoids are mediated by annexin-1 (ANXA1). We investigated the expression of glucocorticoid receptors (GR) and ANXA1, as well as the exogenous effects of ANXA1 on neutrophils in CAD patients, and related the data to diurnal salivary cortisol. Methods and Results: Salivary cortisol levels were measured in the morning and evening during 3 consecutive days in 30 CAD patients and 30 healthy individuals. The neutrophil expression of GR and ANXA1 was determined by flow cytometry. The effect of exogenous ANXA1 was determined in a neutrophil stimulation assay. The patients showed a flattened diurnal cortisol pattern compared with healthy subjects, involving higher levels in the evening. The neutrophil expression of GR-total and GRα was decreased, whereas the GR-β expression did not differ compared with controls. The neutrophil expression of ANXA1 was significantly increased in patients. Ex vivo, ANXA1 impaired the leukotriene B 4-induced neutrophil production of reactive oxygen species in patients but not in controls. Conclusion: Our findings indicate a persistent overactivation of the hypothalamic-pituitary-adrenal axis in CAD patients but do not give any evidence for glucocorticoid resistance, as assessed by the neutrophil expression of GR and ANXA1. The altered neutrophil phenotype in CAD may thus represent a long-term response to disease-related activation.
The Journal of Clinical Endocrinology & Metabolism, 2005
Central obesity, insulin resistance, inflammation, as well as vascular changes are common in patients with type 2 diabetes. In this study we assessed the relationship among stiffness of the carotid artery, visceral fat, and circulating inflammatory markers in type 2 diabetic subjects. Carotid stiffness, quantified as the distensibility coefficient (DC), was measured by ultrasound in asymptomatic, normotensive patients with uncomplicated, well-controlled type 2 diabetes and in controls. Body fat distribution was quantified by magnetic resonance imaging. In patients, the carotid DC was inversely associated with visceral fat area (r ؍ ؊0.660; P ؍ 0.005) and plasma levels of C-reactive protein (CRP; r ؍ ؊0.687; P ؍ 0.002), but most strongly with plasma IL-6 (r ؍ ؊0.766; P < 0.001). In multivariate analysis, the association between DC and visceral fat disappeared after adjustment for CRP and IL-6. Correction for age, body mass index, blood pressure, glycosylated hemoglobin, or fasting plasma glucose did not affect the association between carotid DC and inflammatory markers. Thus, carotid stiffness is associated with visceral obesity in patients with uncomplicated type 2 diabetes, but this association seems to be mediated by circulating IL-6 and CRP, of which IL-6, at least in part, originates from adipose tissue and stimulates hepatic CRP production. (J Clin Endocrinol Metab 90: 1495-1501, 2005)