Ticagrelor: a cardiometabolic drug targeting erythrocyte-mediated purinergic signaling?

2021 ◽  
Vol 320 (1) ◽  
pp. H90-H94
Author(s):  
Bernhard Wernly ◽  
David Erlinge ◽  
John Pernow ◽  
Zhichao Zhou
Keyword(s):  
Drug Targeting ◽  
Purinergic Signaling ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Pleiotropic Effect ◽  
Cardiovascular Complications ◽  
Coronary Syndrome ◽  
Adenosine Uptake ◽  
Underlying Mechanisms

Cardiometabolic diseases lead to vascular complications, which cause increasing morbidity and mortality worldwide. The underlying mechanisms are multifactorial and complex but may involve altered purinergic signaling that significantly contributes to cardiovascular dysfunction. Ticagrelor is a successful purinergic drug directly targeting ADP-mediated P2Y12R signaling for platelet aggregation and is widely used in patients with acute coronary syndrome. In addition, ticagrelor can target red blood cells (RBCs) to release ATP and inhibit adenosine uptake by RBCs, which subsequently activate purinergic signaling. This involvement in purinergic signaling may allow ticagrelor to mediate pleiotropic effects and contribute to the beneficial cardiovascular outcomes observed in clinical studies. Recent studies have established a novel function of RBCs, which is that RBCs act as disease mediators for the development of cardiovascular complications in type 2 diabetes (T2D). RBC-released ATP is defective in T2D, which has implications for the induction of vascular dysfunction by dysregulating purinergic signaling. Ticagrelor might target RBCs and restore the bioavailability of ATP and adenosine, thereby attenuating cardiovascular complications. The present perspective discusses the pleiotropic effect of ticagrelor, with a focus on the possibility of ticagrelor for the treatment of cardiometabolic complications by targeting RBCs and initiating purinergic activation. A better understanding of the proposed cardiometabolic effects could support novel clinical indications for ticagrelor application.

scholarly journals Purinergic interplay between erythrocytes and platelets in diabetes-associated vascular dysfunction

2021 ◽  
Author(s):  
Zhichao Zhou
Keyword(s):  
Type 2 Diabetes ◽  
Blood Cells ◽  
Cardiovascular Events ◽  
Purinergic Signaling ◽  
Vascular Dysfunction ◽  
P2y Receptors ◽  
Receptor Activation ◽  
Cardiovascular Complications ◽  
High Morbidity

AbstractCardiovascular complications in diabetes are the leading causes for high morbidity and mortality. It has been shown that alteration of purinergic signaling contributes to diabetes-associated cardiovascular complications. Red blood cells (RBCs) and platelets play a fundamental role in regulation of oxygen transport and hemostasis, respectively. Of note, these cells undergo purinergic dysfunction in diabetes. Recent studies have established a novel function of RBCs as disease mediators for the development of endothelial dysfunction in type 2 diabetes (T2D). RBC-released ATP is defective in T2D, which has implication for induction of vascular dysfunction by dysregulating purinergic signaling. Platelets are hyperactive in diabetes. ADP-mediated P2Y1 and P2Y12 receptor activation contributes to platelet aggregation and targeting P2Y receptors particularly P2Y12 receptor in platelets is effective for the treatment of cardiovascular events. In contrast to other P2Y12 receptor antagonists, platelet-targeting drug ticagrelor has potential to initiate purinergic signaling in RBCs for the beneficial cardiovascular outcomes. It is increasingly clear that altered vascular purinergic signaling mediated by various nucleotides and nucleoside contributes to diabetes-associated vascular dysfunction. However, the contribution of complex purinergic networks between RBCs and platelets to the vascular dysfunction in diabetes remains unclear. This study discusses the possible interplay of RBCs and platelets via the purinergic network for diabetes-associated vascular dysfunction.

Mechanisms underlying heart failure in type 2 diabetes mellitus

2019 ◽  
pp. 37-39
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Experimental Studies ◽  
Vascular Complications ◽  
Molecular Alterations ◽  
Increased Risk ◽  
Cardioprotective Effects ◽  
Underlying Mechanisms ◽  
Cardio Vascular

The prevalence of heart failure is markedly increased in individuals with diabetes mellitus. Numerous observational studies suggest that this increased risk for heart failure can be attributed to exacerbated vascular complications and the presence of increased risk factors in diabetic subjects. In addition, experimental studies revealed the presence of a number of distinct molecular alterations in the myocardium that occur independently of vascular disease and hypertension. Many of these molecular alterations are similarly observed in failing hearts of nondiabetic patients and have thus been proposed to contribute to the increased risk for heart failure in diabetes. The interest in understanding the underlying mechanisms of impaired cardio- vascular outcomes in diabetic individuals has much increased since the demonstration of cardioprotective effects of SGLT-2 inhibitors and GLP-1 receptor agonists in recent clinical trials. The current review therefore summarizes the distinct mechanisms that have been proposed to increase the risk for heart failure in diabetes mellitus.

scholarly journals Differential Telomere Shortening in Blood versus Arteries in an Animal Model of Type 2 Diabetes

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Samira Tajbakhsh ◽  
Kamelya Aliakbari ◽  
Damian J. Hussey ◽  
Karen M. Lower ◽  
Anthony J. Donato ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Sirtuin 1 ◽  
Telomere Shortening ◽  
Telomere Attrition ◽  
Clinical Complications

Vascular dysfunction is an early feature of diabetic vascular disease, due to increased oxidative stress and reduced nitric oxide (NO) bioavailability. This can lead to endothelial cell senescence and clinical complications such as stroke. Cells can become senescent by shortened telomeres and oxidative stress is known to accelerate telomere attrition. Sirtuin 1 (SIRT1) has been linked to vascular health by upregulating endothelial nitric oxide synthase (eNOS), suppressing oxidative stress, and attenuating telomere shortening. Accelerated leukocyte telomere attrition appears to be a feature of clinical type 2 diabetes (T2D) and therefore the telomere system may be a potential therapeutic target in preventing vascular complications of T2D. However the effect of T2D on vascular telomere length is currently unknown. We hypothesized that T2D gives rise to shortened leukocyte and vascular telomeres alongside reduced vascular SIRT1 expression and increased oxidative stress. Accelerated telomere attrition was observed in circulating leukocytes, but not arteries, in T2D compared to control rats. T2D rats had blunted arterial SIRT1 and eNOS protein expression levels which were associated with reduced antioxidant defense capacity. Our findings suggest that hyperglycemia and a deficit in vascular SIRT1per seare not sufficient to prematurely shorten vascular telomeres.

scholarly journals Effect of Hyperglycemia on Epcs Function and Regenerative Ability

2020 ◽  
Author(s):  
Hadeel Khalil Hendawi ◽  
Dina Nehad Awartani ◽  
Aya Ghoul ◽  
Isra Marei
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Barrier Function ◽  
Vascular Endothelial Cells ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Diabetic Patients ◽  
Vascular Endothelial ◽  
Cell Functions

Diabetes induced hyperglycemia increases the risk of cardiovascular complications as it impacts vascular endothelial cells causing vascular dysfunction. Endothelial progenitor cells (EPCs) have been suggested to participate in the repair of vascular endothelial cells once they are impacted by hyperglycemia in diabetic patients. This research aims to test the EPC subtype blood outgrowth endothelial cells (BOECs) and their ability to survive and function under chronic hyperglycemic conditions. For that, we studied BOECs viability, response to shear stress, angiogenesis ability, and barrier function under normoglycemic (5.5mM) and hyperglycemic (25mM) conditions. The results have shown significant effects of chronic hyperglycemic conditions on cell proliferation (n=3, p<0.05), and migration (n=3, p<0.05) which were decreased when compared to control. Cells responses to shear stress were not affected under these conditions. There was a trend towards an increase in permeability as indicated by barrier function assays. The decrease in those endothelial cell functions might impact the repair mechanisms needed in diabetic patients to protect from vascular complications. Further investigations are required to establish therapeutic targets to improve EPCs repair function.

scholarly journals Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

2019 ◽  
Vol 20 (15) ◽  
pp. 3775 ◽  
Author(s):  
Cesar A. Meza ◽  
Justin D. La Favor ◽  
Do-Houn Kim ◽  
Robert C. Hickner
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Blood Flow ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Enzymatic Production

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.

Abstract MP250: Reduction In Endothelial Aryl Hydrocarbon Receptor Nuclear Translocator (arnt) Mediates Vascular Dysfunction In Mice With Type 2 Diabetes Mellitus

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Tu Nguyen ◽  
Kaichao Pan ◽  
Maura Knapp ◽  
Mei Zheng ◽  
Nikola Sladojevic ◽  
...  
Keyword(s):  
Cell Viability ◽  
High Glucose ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Tube Formation ◽  
Diabetic Mice ◽  
Aryl Hydrocarbon ◽  
Diabetic Vascular Complications ◽  
High Fat Chow

Background: Endothelial dysfunction, especially at the microvasculature level, is one of the most deleterious events in diabetes. ARNT is a transcription factor that functions as a master regulator of glucose homeostasis, but its role in diabetic vascular complications is poorly understood. Results and method: We found a reduction in ARNT expression in microvascular endothelial cells (MVECs) derived from type 2 diabetic mice (db/db). Thus, we generated an inducible, EC-specific ARNT-knockout mutation ( Arnt ΔEC, ERT2) to address the hypothesis that aberrations in ARNT expression might contribute to the vascular deficiencies associated with diabetes. We show here that loss of ARNT in the endothelium mimics diabetic phenotypes, such as impairs blood flow recovery after hindlimb ischemia, delays wound healing, and exacerbates infiltration of pro-inflammatory neutrophils after myocardial infarction. Interestedly, the degree of these impairments in the KO mice was more remarkable in diabetic animals induced with high-fat chow. In addition, the siRNA-mediated knockdown of ARNT activity reduced tube formation and cell viability measurements in HUVECs cultured under high-glucose conditions. The Arnt ΔEC, ERT2 mutation also reduced measures of cell viability while increasing the production of reactive oxygen species (ROS) in MVECs isolated from mouse skeletal muscle, and the viability of Arnt ΔEC, ERT2 MVECs under high-glucose concentrations increased when the cells were treated with a ROS inhibitor. Conclusion: Collectively, these observations suggest that declines in endothelial ARNT expression contribute to the suppressed angiogenic phenotype in diabetic mice and that the cytoprotective effect of ARNT expression in ECs is at least partially mediated by declines in ROS production. Endothelial ARNT might be a critical mediator of endothelial function and could serve as a therapeutic target for diabetic complications.

scholarly journals The protean role of haptoglobin and haptoglobin genotypes on vascular complications in diabetes mellitus

2018 ◽  
Vol 25 (14) ◽  
pp. 1502-1519 ◽  
Author(s):  
Rinkoo Dalan ◽  
Goh Liuh Ling
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Vitamin E ◽  
Clinical Studies ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Diabetes Patients

Introduction and background Haptoglobin (Hp) is considered to be an antioxidant and protective against cardiovascular complications. Polymorphisms in the Hp gene interact with diabetes mellitus to affect the risk of vascular complications. Methods We review the updated literature about the protean role of Hp and Hp genotypes spanning genomics, molecular, translational and clinical studies. We searched Pubmed, SCOPUS and Google Scholar for all articles using the keywords: haptoglobin and/or haptoglobin polymorphism and diabetes. We review the diverse Hp genotypes, phenotypes and the impact on diabetes complications, including lessons from animal models and in vitro models. We describe the clinical studies on the associations of Hp genotypes with vascular complications in type 1 and type 2 diabetes comprehensively. We review the studies looking at vitamin E supplementation in a personalized manner in Hp2-2 diabetes individuals. Results and conclusion Hp genotypes have evolved as a result of deletions in the traditional Hp genes. The Hp genotypes have been associated with microvascular and macrovascular complications in type 1 diabetes mellitus but the association in type 2 diabetes is more consistent with cardiovascular complications. A preferential benefit of vitamin E and other antioxidants in the Hp2-2 genotype for cardiovascular complications in type 2 diabetes has been seen presumably secondary to interaction with high-density lipoprotein function. Hence, the Hp genotype can be used to personalize antioxidant therapeutics in diabetes patients. These results need to be corroborated in large, global, pragmatic, prospective, cardiovascular outcome trials in type 2 diabetes patients.

scholarly journals Current Data Regarding the Relationship between Type 2 Diabetes Mellitus and Cardiovascular Risk Factors

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 314 ◽  
Author(s):  
Cosmin Mihai Vesa ◽  
Loredana Popa ◽  
Amorin Remus Popa ◽  
Marius Rus ◽  
Andreea Atena Zaha ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cardiovascular Risk ◽  
Cardiovascular Complications ◽  
Current Data ◽  
Coronary Syndrome ◽  
Cardiovascular Morbidity And Mortality ◽  
Severe Atherosclerosis ◽  
Artery Disease ◽  
The Moment

Reducing cardiovascular risk (CVR) is the main focus of diabetes mellitus (DM) management nowadays. Complex pathogenic mechanisms that are the subject of this review lead to early and severe atherosclerosis in DM patients. Although it is not a cardiovascular disease equivalent at the moment of diagnosis, DM subjects are affected by numerous cardiovascular complications, such as acute coronary syndrome, stroke, or peripheral artery disease, as the disease duration increases. Therefore, early therapeutic intervention is mandatory and recent guidelines focus on intensive CVR factor management: hyperglycaemia, hypertension, and dyslipidaemia. Most important, the appearance of oral or injectable antidiabetic medication such as SGLT-2 inhibitors or GLP-1 agonists has proven that an antidiabetic drug not only reduces glycaemia, but also reduces CVR by complex mechanisms. A profound understanding of intimate mechanisms that generate atherosclerosis in DM and ways to inhibit or delay them are of the utmost importance in a society where cardiovascular morbidity and mortality are predominant.

scholarly journals Economic evaluation of type 2 diabetes mellitus burden and its main cardiovascular complications in the Russian Federation

2016 ◽  
Vol 19 (6) ◽  
pp. 518-527 ◽  
Author(s):  
Ivan I. Dedov ◽  
Anna V. Koncevaya ◽  
Marina V. Shestakova ◽  
Yuriy B. Belousov ◽  
Julia A. Balanova ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Russian Federation ◽  
Complex Analysis ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Permanent Disability ◽  
Clinical Investigations ◽  
The Russian Federation ◽  
Cardio Vascular

Background. Diabetes Mellitus Type 2 (DMT2) is a complex medical and social problem in the world and in the Russian Federation also due to prevalence and probability of cardio-vascular complications (CVC).Aim. Economic burden evaluation of DMT2 in the Russian Federation.Methods. Complex analysis of expenditures (direct and non-direct costs) based on epidemiological, pharmacoeconomics and clinical investigations, population and medical statistics data.Results. Calculated expenditures for DMT2 are 569 bln RUR per year, that is correspond to 1% of the Russian GDP, and 34,7% of that are expenditures for main CVC (ischemic heart disease, cardiac infarction, stroke). Main part of expenses are non-medical (losses GDP) due to temporary and permanent disability, untimely mortality – 426,7 bln RUR per year. Expenditures in estimated group of patients with non-diagnosed DMT2 but with already having CVC were at least 107 bln per year (18,8% from total cost). Relationship between cost of DMT2 and degree of it’s control was found in the Russian conditions. Estimated cost for compensated patient (HbA1c6,5%) per year was 88 982 RUR, in the same time cost of non-control patient (HbA1c9,5%) was in 2,8 times higher due to more often main CVC in this group.Conclusion. DMT2 diagnosis improvement as well as effective treatment of early stages of illness can decrease probability of CVC and social economic expenditures. 

scholarly journals Different antihyperglycaemic drug effects on glycaemic variability in Type 2 diabetic patients

2014 ◽  
Vol 17 (4) ◽  
pp. 72-80 ◽  
Author(s):  
Alina Babenko ◽  
Elena Ivanovna Krasilnikova ◽  
Nikolay Pavlovich Likhonosov ◽  
Anna Pavlovna Likhonosova ◽  
Elena Nikolaevna Grineva
Keyword(s):  
Treatment Strategies ◽  
Vascular Complications ◽  
Drug Effects ◽  
Glycated Haemoglobin ◽  
Cardiovascular Complications ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Glycaemic Variability ◽  
Beneficial Effects

Optimizing treatments for type 2 diabetes mellitus (T2DM) remains an urgent issue. In addition to T2DM treatment strategies, such as glycaemic goals (glucose and glycated haemoglobin ? HbА1c) among different patient populations, the influence of glycaemic variability (GV) on the prognosis of patients with T2DM is also important. According to recent data, GV is associated with cardiovascular complications arising from T2DM. However, although the influence of GV on the development of vascular complications arising from diabetes and underlying mechanisms has been extensively investigated, few studies have investigated the effects of different glucose-lowering medications on GV, and there are even fewer reviews of this topic. This type of analysis is highly relevant, particularly because new classes of antidiabetic medications with potent glucose-dependent insulinotropic effects have been developed. These include groups of drugs that mimic or enhance incretin activity, such as glucagon-like peptide (GLP)-1 analogues/mimetics and dipeptidyl peptidase (DPP)-4 inhibitors. A glucose-dependent mechanism suggests that these groups of antidiabetic medications have beneficial effects on GV. Thus, the current study focusses on the comparative analysis of drugs based on their incretin effects (GLP-1 analogues/mimetics and DPP-4 inhibitors) and оther antidiabetic medications with regard to GV in the patients with T2DM.

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