Endothelial Dysfunction and Oxidative Stress Influencing Thrombosis: Comparison
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Please note this is a comparison between Version 2 by Wendy Huang and Version 1 by Tim Palmer.

The leading causes of death in people with diabetes are strokes and cardiovascular disease. Significant morbidity is associated with an increased risk of thrombosis, resulting in myocardial infarction, ischaemic stroke, and peripheral vascular disease, along with the sequelae of these events, including loss of functional ability, heart failure, and amputations. While the increased platelet activity, pro-coagulability, and endothelial dysfunction directly impact this risk, the molecular mechanisms linking poor glycaemic control with increased thrombotic risk remain unclear.

  • diabetes
  • thrombosis
  • platelet
  • cardiovascular disease
  • endothelial dysfunction
  • oxidative stress

1. Introduction

Diabetes is a chronic metabolic disease characterised by elevated levels of blood glucose due to the body’s impaired ability to produce or respond to the hormone insulin. The number of adults living with diabetes is estimated to be over 420 million, with its prevalence predicted to increase to become the seventh leading cause of global deaths by 2030. The majority of those with a diagnosis of diabetes have type 2 diabetes mellitus (T2DM) [1]. Evidence has shown that the NHS spends around GBP 10 billion a year on diabetes care, equating to around 10% of the entire budget [2]. As the incidence of T2DM is projected to increase significantly over the next 10–15 years, the effective prevention and management of diabetes pose a significant challenge for health and social care systems under increasing pressure from an ageing population in which it is a common co-morbidity [3].
People with diabetes have a 2–4-fold increased risk of developing cardiovascular disease (CVD) and stroke. Approximately 80% of people with diabetes will die of atherothrombotic CVD [4], including major cardiovascular events (MACE), such as acute myocardial infarction (MI) and ischaemic stroke, occurring when platelets aggregate at sites of blood vessel damage to form blood clots, interrupting blood flow and causing tissue hypoperfusion. Poor glycaemic control is known to lead to adverse cardiovascular outcomes, including the increased risk of thrombosis [5].
Multiple mechanisms contribute to the increased risk of thrombosis in diabetes, including activation of coagulation pathways, endothelial dysfunction, and alteration of signalling pathways, leading to an increase in the adhesion, activation, and aggregation of platelets [6]. While high blood glucose can predict susceptibility to CVD, direct mechanisms linking high blood glucose levels associated with poorly controlled diabetes with increased platelet aggregation are unclear.
Hyperglycaemia, a major feature used to determine poor diabetic control, is the main focus of improving clinicians’ management. Rather than a single glucose measurement, the focus has moved to measuring glycated haemoglobin levels (HbA1c), which gives an average blood glucose reading over the life cycle of the red blood cell—usually 8–12 weeks [7]. A person can be diagnosed as having diabetes with an HbA1c level of ≥48 mmol/mol. There is no specific definition of what constitutes “poor control” of diabetes. An HbA1c of >63.9 mmol/mol (8% DCCT, average blood glucose 10.1 mmol/L) is generally used in the USA [8], whereas >53 mmol/mol (7% DCCT, average blood glucose 8.6 mmol/L) is suggested by The National Institute for Health and Care Excellence (NICE) [9]. Targets are based on appropriateness, judged by individual assessment and by weighing up individual risks, particularly of hypoglycaemia. Antiplatelet medications remain the mainstay of treatment strategies for both primary and secondary prevention of MACE. Despite guidelines detailing when these drugs should be utilised in diabetes, eligible subjects often miss out on these important medications with the potential for devastating results [10]. With regards to surgical intervention for MACE, such as coronary artery bypass surgery, it has been shown in large studies that both short and long-term outcomes are worse in those with diabetes [11].

2. Endothelial Dysfunction

Endothelial cells, which line the lumen of all blood vessels, act as a cellular monolayer between the blood and underlying vascular smooth muscle cells. The endothelium has a critical role in homeostasis, regulating blood flow by undergoing vasodilation and vasoconstriction, preventing blood loss as well as having pro and anti-inflammatory effects. An imbalance in any of these factors triggers a shift in endothelial cells from a predominantly anti-inflammatory and anti-thrombotic phenotype to a dysfunctional pro-inflammatory and pro-thrombotic one [12]. Hyperglycaemia causes oxidative stress, resulting in raised levels of glycated proteins and lipids. Advanced glycated end products (AGEs) are proteins or lipids that become glycated and oxidised through a non-enzymatic reaction with glucose or other glycating compounds, such as 3-deoxyglucosone, methylglyoxal, and glyoxal, produced from an increase in fatty acid oxidation [13,14][13][14]. This post-translational modification can disrupt the normal functioning of biological processes and is associated with many diseases, including diabetes [15]. Increased levels of AGE and the subsequent modifications of proteins are known to not only play a causative role in cardiovascular complications, such as atherosclerosis and peripheral vascular disease [16], in diabetes but also correlate with the severity of diabetic complications [17]. Damage as a result of AGE modification can occur in multiple ways—by altering the specific function of a protein, modifying the extracellular matrix, resulting in an interaction with matrix receptors on the surface of vascular endothelial cells, and also binding to AGE receptors (RAGE) on macrophages and endothelial cells [14]. RAGE activation results in the activation of multiple transcription pathways, including transcription factor nuclear factor-κB—a universal transcription factor involved in inflammatory and immune responses, which ultimately results in the upregulation of inducible nitric oxide synthase (iNOS) [15,18][15][18]. RAGE activation on vascular endothelial cells triggers activation of the coagulation pathway, pro-inflammatory cytokines (such as interleukin-1, interleukin-6, and tumour necrosis factor-alpha), which induce endothelial tissue factor, and the chemokine monocyte chemoattractant protein-1 [19,20][19][20]. Medications used to improve blood glucose control improve outcomes in people with diabetes. Metformin works by not only improving glycaemic control by improving the body’s response to glucose but also inhibiting AGE formation in renal tubular cells [21,22][21][22].

3. Oxidative Stress

Oxidative stability is the balance between the rate of free radical formation and elimination and is important in healthy individuals. A decrease in the elimination or an increase in the production results in free radicals and subsequent tissue damage termed oxidative stress [24][23]. Reactive oxygen species (ROS) are produced during reduction–oxidation reactions in the progression from O2 to H2O. The superoxide anion (O2•−) influences vascular function and serves as a precursor to most other ROS. Superoxide dismutase (SOD) catalyses the conversion of O2•− into hydrogen peroxide (H2O2) by partitioning. Partial reduction of H2O2 forms hydroxyl radicals (OH•). Catalase and glutathione peroxidase (GPx) fully reduce H2O2 to H2O. Myeloperoxidase (MPO) metabolism of H2O2 produces a hypochlorous acid [25][24]. In diabetes, oxidative stress is thought to be a major contributor to the development of diabetic complications due to the increased production of free radicals in states of hyperglycaemia [26][25]. The link between hyperglycaemia-induced oxidative stress and complications in diabetes is complex, and four hypotheses have been suggested to explain this: increased polyol (sorbitol) pathway flux, increased AGE formation, activation of protein kinase C (PKC) isoforms, and increased hexosamine pathway flux [27,28,29][26][27][28]. Glycaemic variability has also been shown to increase morbidity by increasing the risk of diabetic complications, which may not be apparent when looking at overall diabetes control using current methods, such as HbA1c monitoring [30,31][29][30]. These intermittent swings of high glucose have been shown to cause an increase in oxidative stress and endothelial dysfunction. Overall, glycaemic control seen in poorly controlled diabetes (including hyperglycaemia and glycaemic variability) leads to an increase in ROS and suppression of host antioxidant defence systems [28][27]. The disruption in oxidative equilibrium is believed to contribute to nervous degeneration, leading to peripheral diabetic neuropathy [32][31]. Damage to DNA from oxidative stress prompts excessive activation of the nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP-1). A study conducted by Obrosova et al. (2009) demonstrated that inhibiting PARP alleviated dysfunction and degeneration in small sensory nerve fibres [33][32].

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