How Might Hyperglycemia Contribute to the Development of Atherosclerosis - Coursework Example

HOW MIGHT HYPERGLYCEMIA CONTRIBUTE TO THE DEVELOPMENT OF ATHEROSCLEROSIS? How might Hyperglycemia contribute to the development of atherosclerosis? Hyperglycemia caused by uncontrolled glucose regulation is considered as a significant causal link between diabetes and diabetic complications. Both type 1 and type 2 diabetes are strong and independent risk factors for stroke, peripheral arterial disease and coronary artery disease (Aronson & Rayfield 2002). Atherosclerosis accounts for 80% of the mortality rates among the diabetic patients. It has been established through scientific data that the prolonged exposure to hyperglycemia is a major risk factor that leads to the pathogenesis of atherosclerosis. The pathogenesis is multifactorial and can be affected by metabolic stress, oxidative stress, inflammation and other factors. Type 2 Diabetes is the most prevalent and serious metabolic disease affecting people worldwide and is marked by pancreatic B-cell dysfunction and insulin resistance (Kaneto, et al., 2006). The high levels of circulating glucose is associated with increased risk of endothelial dysfunction, oxidative stress, increased protein kinase C activity and activation of an inflammatory process, which are all involved in the process of atherosclerosis. The three major pathological alterations observed in the hyperglycemic vasculature include non-enzymatic glycosylation of proteins and lipids, oxidative stress and protein kinase C activity (Aronson & Rayfield, 2002). These mechanisms are interrelated and play a significant role in the theory of atherogenesis. One of the most important mechanisms associated with diabetes is the non-enzymatic reaction between glucose and proteins or lipoproteins in arterial walls. This process is collectively known as browning reaction or Maillard reaction. Glucose forms reversible bonds with the reactive amino groups of circulating proteins or the proteins of the vessel walls. These early linkages are then rearranged to form more stable glycosylation products. Early glycosylation products which are present in association with long-lived proteins such as vessel wall collagen continue to form complex chemical rearrangements, eventually resulting in the formation of advanced glycosylation end products (AGEs) (Aronson & Rayfield, 2002). The AGEs are the chemotactic agents for human blood monocytes and induce monocyte migration across an endothelial cell monolayer. The receptors for the AGEs are present on the endothelium and result in the alteration of the cell surface structures. This can lead to the alteration of the anticoagulant endothelium into a procoagulant endothelium. AGEs may also contribute to the expression of oxidized LDL receptors in the monocyte derived macrophages. This leads to increased uptake of LDL by the macrophages forming foam cells, characteristic feature of atheroma plaque (Goldin, et al., 2006). Fig1. The binding of the advanced glycation end products to the receptors leads to increased oxidative stress in the endothelial cells, hence activating the vascular cell adhesion molecules (VCAM-1) on the surface, leading to monocyte adhesion and atherogenesis (Aronson & Rayfield, 2002). High glucose levels in the blood activate the protein kinase C by increasing the diacylglycerol (DAG) from the glycolytic intermediates such as glyceraldehyde-3-phosphate. It has been observed that there is a preferential activation of PKC in aorta, retina, heart and the glomeruli. PKC activation leads to transcription of growth factors such as increased platelet derived growth factor-B receptor expression on the smooth muscle cells and on the vascular wall cells, which is an initiating factor for atherosclerosis (Aronson & Rayfield, 2002). A major pathway for the production of oxidative stress is by the reactive oxygen species produced by the proton electromechanical gradient generated by the mitochondrial electron transport chain, which leads to increased production of superoxide. Oxidative stress may also be involved in the activation of the DAG-PKC in the vascular tissue and it has been shown that antioxidants such as Vitamin E can inhibit PLC activation (Aronson & Rayfield, 2002; Kaneto, et al., 2006). Fig.2) Insulin resistance is associated with reduced eNOS activation and increase in VCAM-1 expression by the endothelium cells. The net effect is endothelial dysfunction and activation leading to impaired vasodilation and entry of inflammatory cells into the plaque (Bornfledt & Tabas, 2011). Blood flow induced shear stress is an essential feature of atherogenesis. “Shear stress is the resulting tangential force due to blood flow across the endothelium and is important for the release of vasoactive substances such as nitric oxide, gene expression and, and cell metabolism” (Thosar, et al., 2012). The fluid drag force which acts on the vessel wall is mechano-transduced into a biochemical signal that leads to alterations in vascular behaviour. It is important to maintain a laminar shear stress which is physiological so that a normal vascular functioning is attained. This involves the prevention of proliferation of the smooth muscles in response to endothelium injury and inflammation of the vessel wall (Cunningham & Gotlieb, 2005). Vascular endothelium has different responses at molecular and cellular level to the distributed shear stress on the endothelium cells. Shear stress is vital in regulating the athero-protective, normal physiology as well as the pathobiology and dysfunction of the vessel wall through complex molecular mechanisms that lead to atherogenesis. Areas of high shear stress have preserved endothelial function and are protected from atherosclerosis, whereas vessels with low shear stress are exposed to pathology. Insulin sensitivity and increased blood flow (increased shear stress) are important factors in maintaining a healthy endothelium. Similarly, reduced blood flow or sensitivity to insulin leads to lower levels of nitric oxide bioavailability and weakens endothelial function, thus generating a pro-atherogenic setting (Thosar, et al., 2012). Fig.3) Reduced shear stress or turbulent blood flow leads to endothelial injury and release of endothelial particles. Nitric oxide bioavailability is reduced leading to oxidative stress and the pro-atherosclerotic environment (Thosar, et al., 2012). Cross mark indicates reduction or blockage of certain function of process. It has been postulated that pathogenesis of diabetes mellitus type 2 is associated with the innate immune system which causes the cytokine mediated acute phase response. Studies have revealed the presence of circulating markers IL-6 and tumor necrosis factor- α (TNF- α) elevated in individuals with insulin resistance and clinically evident diabetes mellitus. It has been shown through studies that acute hyperglycemia induces an increase in plasma IL-6, TNF- α and IL-18 concentrations. However, it has been also noticed that the cytokine concentrations are more associated with hyperglycemic spikes rather than continuous hyperglycemia. The antioxidant glutathione plays a major role in preventing the rise in the circulating cytokines associated with hyperglycemic spikes. Epidemiological studies have shown that postprandial rise in blood glucose in diabetics is a strong risk factor for cardiovascular disease as compared to the fasting hyperglycemia. IL-18 cytokine is a significant cytokine involved in atherogenesis and induces the expression of adhesion molecules along with stimulating the production of granulocyte-macrophage colony-stimulating factor (Esposito, et al., 2002). IL-18 is also involved atherosclerotic plaque destabilization which can lead to acute ischemic syndrome in previously asymptomatic plaques. Inflammatory cytokine stimulation also leads to the production of nitric oxide. The overproduction of nitric oxide by induction of eNOS, explains the impairment of both muscle cell insulin action as well as the B cell function in obesity, consequently leading to insulin resistance (Wellen & Hotamisligil, 2005). High levels of blood glucose increase the eNOS gene expression, protein expression and ultimately nitric oxide release. However, the overproduction of nitric oxide is also associated with marked increase of oxygen free radical O2−. Due to the oxidant stress in the endothelial cells, the endothelium cells exhibit impaired arachidonic acid metabolism, lipid peroxidation and prostanoid production. In arteries, prolonged exposure to high glucose levels lead to impaired endothelial-dependant relations. Superoxide anions are involved in glucose-induced changes in endothelial Ca/ endothelium derived relaxing factor signalling. The free radical produces contractile effects by formation of hydrogen peroxide and hydroxyl radical (Cosentino, et al., 1997; Niebauer & Cooke, 1996). One possible explanation for the increased expression of the eNOS gene is the formation of diacylglycerol as well as protein kinase C activation, which is chronically activated in the diabetic patients (Cosentino, et al., 1997). (Fig. 4) Nitric oxide is the major endothelium derived substance and the hallmark of endothelial dysfunction is the impaired endothelium-dependant vasodilation, which is mediated by NO. Nitric oxide is formed from its L-arginine via the the enzymatic action of endothelial NO synthase (Davignon & Ganz, 2004). Inflammation plays an active role in all stages of atherosclerosis and hence is strongly linked to the inflammatory cytokines produced by the hyperglycemic state. Oxidized lipids specifically the low-density lipoprotein retained in the intima, participate in the initiation of atherosclerosis. These modified lipids induce the expression of adhesion molecules, proinflammatory cytokines and chemokines in macrophages and vascular wall cells (Libby, et al., 2002). The lipoprotein particles also produce an antigenic response, inciting the T-cell response and thus activating the antigen specific limb of the immune system. Inflammatory events not only lead to initiation and evolution of atheroma but also contribute to the acute thrombotic complications of atheroma as well. Heightened risk for atherosclerosis progression in response to increased blood glucose and oxidized LDL is linked to the augmented Th1 cytokine profile as well (Libby, et al., 2002; Keren, et al., 2000). The overview of the pathogenesis of the hyperglycemic state and its association with atherosclerosis elaborates several factors which can be therapeutically emphasized for controlling the pro-atherogenic environment. Compounds which inhibit the AGEs such as amnioguanide, are under study, which has shown to increase the arterial elasticity and reduction in extracellular matrix accumulation of both fibronectin and laminin in the experimental diabetic rats. It is also an inhibitor of NOS which may become a offset to its AGE inhibiting benefits (Goldin, et al., 2006). It has also been shown that loss of inflammatory mediators or signalling molecules prevents insulin resistance in mice. Effective treatment has been showed with inhibitors of inflammatory kinases and with agonists of relevant transcription factors (Wellen & Hotamisligil, 2005). Physical exercise has beneficial effects on the cardiovascular health and it has shown to increase blood flow and shear stress, which enhances the vascular function and structure (Niebauer & Cooke, 1996). Strategies should be developed to inhibit the oxidation or glycoxidation in diabetes leading to CVD, imaging and other techniques should be developed to study the endothelial structure and function and the importance of the procoagulant states in to CVD in diabetes should also be studied in detail. References ARONSON, DORON & RAYFIELD, ELLIOT J. (2002). How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovascular Diabetology.1 1475-2840. BORNFLEDT, K. 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