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6 Atherothrombosis and the Metabolic Syndrome. Emma J. Dunn and Peter J. Grant. Introduction. The metabolic syndrome- also known as the insulin resistance syndrome- associated with a cluster of abnormalities including obesity, hypertention, glucose intolerance and dyslipidaemia.
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6 Atherothrombosis and the Metabolic Syndrome Emma J. Dunn and Peter J. Grant
Introduction • The metabolic syndrome- also known as the insulin resistance syndrome- associated with a cluster of abnormalities including obesity, hypertention, glucose intolerance and dyslipidaemia. • Insulin resistance is associated with a significant increase in the risk of developing atherothrombotic disease, which is due in part to a disruption in the balance of factors regulating coagulation and fibrinolysis, the development of endothelial dysfunction and enhanced platelet aggregation and activation.
Insulin resistance and endothelial dysfunction • vascular endothelium function: - maintain vascular homeostasis, physical barrier - regulate vascular tone, platelet adhesion, coagulation, fibrinolysis, and the adherence of leucocyts to its surface • endothelium dysfunction> vasospasm, thrombosis, vessel occlusion, infammation, the pathogensis of atherosclerotic disease, the development of CVD event. • endothelial dysfunction has been found in healthy subjects with insulin resistance and in healthy first-degree relatives of patients.
Insulin resistance and endothelial dysfunction • In both groups the degree of endothelial dysfunction was associated with insulin resistance and visceral obesity. • Interventional study, both weight loss and physical exercise (known to increase insulin sensitivity) are associated with an improvement in endothelial function. • Several components of the metabolic syndrome, such as low levels of HDL particles and elevated free fatty acid levels, are associated with the development of endothelial dysfunction.
Insulin resistance and endothelial dysfunction • Inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and acute-phase protien (CRP) influence endothelial cell function.
The haemostatic mechanism coagulation pathway fibrinolytic pathway
The haemostatic mechanism and insulin resistance • Type 2 diabetes is associated with profound suppression of fibrinolysis due to high levels of the fibrinolytic inhibitor PAI-1. • The fat-laden insulin-resistant adipocyte generates increased amounts of PAI-1, further strengthenning the link between diabetes and suppression of fibrinolysis. • There are weaker but significant associations between insulin resistance and a variety of coagulation factors, including factors VII, XII and XIII B-subunit and fibrinogen.
Plasminogen activator inhibitor-1 • Plasminogen activator inhibitor-1(PAI-1) is a single-chain glycoprotein that belongs to the family of serine protease inhibitors) • It is synthesized by different cell type, including hepatocytes, fibroblasts, adipocytes, endothelial and mononuclear cells, and is present within the αstorage granules of platelets.
Plasminogen activator inhibitor-1 • Elevated PAI-1 may be a very early risk marker for the development of the metabolic syndrome and type 2 diabetes. • In intervention study, PAI-1 levels fell following interventions known to improve insulin sensitivity. • In vitro studies have demonstrated that PAI-1 expression and secretion can be induced by a number of different mediators including the pro-inflammatory cytokines TNF-αandtransforming growth factors (TGF)-β, insulin and growth factors such as insulin growth factor (IGF)-1, VLDL-triglycerides, free fatty acid and glucose.
Plasminogen activator inhibitor-1 • However, in vivo studies have failed to reproduce these findings. • In addition to environmental influences, genetic factors may also contribute to the variation in PAI-1 levels that occurs in association with the metabolic syndrome.
Tissue plasminogen activator(t-PA) • T-PA is a 70-kDa single-chain active serine protease synthesized and secreted by endothelial cell. • In the absence of fibrin, t-PA activates palsminogen at a very slow rate. • As increased t-PA occurs in association with endothelial cell dysfunction and damage, elevated levels may reflect the presence of underlying endothelial damage.
Factor VII • Factor VII is a 50-kDa vitamin K-dependent serine protease synthesize in the liver that is a key component of the extrinsic coagulaion cascade pathway. • High levels may contribute to a pro-thrombotic state, providing a potential mechanism for increase cardiovascular risk. • Facor VII coagulant activity (FVII:c) levels associate with the metabolic syndrome in healthy individuals and in subjects with type 2 diabetes.
von Willebrand factor and factor VIII • von Willebrand factor (vWF) is synthesized and secreted by vascular endothelial cells and megakaryoctes, and functions to promote platelet adhesion to vascular subendothelium exposed following endothelial cell damage. • Facor VIII (FVIII) circulates in plasma in association with vWF, the strong non-covalent association between the two proteins being essential for the maintenance of FVIII integrity. • Elevated leveles of vWF are taken to indicate the presence of underlying endothelial dysfunction, and correlate with a variety of other cardiovascular risk factors.
von Willebrand factor and factor VIII • The mechanism linking elevated levels of vWF/FVIII to the metabolic syndrome maybe related to the presence of underlying endothelial dysfunction and/or inflammation, both of which have been proposed as being involved in the development of metabolic syndrome.
Fibrinogen • Fibrinogen is a heterodimer composed of three pairs of non-identical polypeptide chains Aα, Bβand γsynthesized by the liver. • Plasma levels influence thrombogensis, affecting the rheology of blood flow, blood viscosity and platelet aggegation, and elevated levels have been shown consistently to be a strong and independent cardiovascular risk factor in prospective epidemiological studies.
Factor XII • Factor XII is a serine protease synthesized in the liver and is involved in the early contact phase of the intrinsic coagulation pathway. • Baseline levels of activated factor XII (XIIa) were associated with a number of conventional cardiovascular risk factors in a population of healthy middle-aged men, including some that cluster in the metabolic syndrome, suggesting its potential usefulness as a marker of atherosclerotic vascular damage.
Factor XIII • Factor XIII is a heterologous glycoprotein composed of two 83-kDa A-subunits and two 79-kDa B-subunits held together by non-covalent association, with the B-subunits serving as a carrier for the catalytic A-subunits. • Factor XIII B-subunit leveles correlate with features of the metabolic syndrome in both healthy South-Asian subjects and in the first –degree relatives of subjects with type 2 diabetes.
Platelets and the metabolic syndrome • Platelets normally function to form a haemostatic plug that seals holes within the walls of damaged blood vessels, enabling wound healing to progress. • They adhere to the vascular subendothelium exposed following endothelial cell damage, whereupon they become activated, releaseing storage granules and aggregating to form thrombi. • The adhesion/aggregation of platelets is regulated by the balance between pro-aggregants and anti-aggregants within the circulation.
Platelets and the metabolic syndrome • Platelet function is also regulated by insulin acting via cell surface receptors. • Insulin has been shown in both in vivo and in vitro studies to antagonize the platelet activating/aggregating effects of a number of agonists, including ADP, platelet activating factor and collagen. • Hyperinsulinaemia in association with the metabolic syndrome might be expected to have a protective role against atherothrombotic disease.
Platelets and the metabolic syndrome • However, in vivo studies have demonstrated that plateles in insulin-resistant subjects are resistant to the action of insulin, NO and PGI2. • Insulin decreases the intracellular concentration of calcium in platelet from insulin-sensitive subjects in vivo and in vitro, it appears to increase the intraplatelet calcium concentrations in insulin-resistant subjects, promoting platelet aggregation and activation. • The loss of insulin’s regulating action over platelet aggregation and activation in insulin resistance could contribute to the enhanced atherothrombotic risk associated with the metabolic syndrome.
