Endothelial dysfunction – A predictor of atherosclerosis

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  Endothelial dysfunction – A predictor of atherosclerosis
   Internet Journal of Medical Update, Vol. 4, No. 1, January 2009 Review   Copyrighted © by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from http://www.geocities.com/agnihotrimed    33 Endothelial dysfunction – A predictor of atherosclerosis Dr. Namrata Chhabra MD   Additional Professor, Department of Biochemistry, S. S. R. Medical College, Mauritius (Received 01 September 2007 and accepted 12 July 2008) ABSTRACT: Endothelial dysfunction is a systemic disorder and a critical element in the pathogenesis of atherosclerotic diseases and its complications. Growing evidences suggest that the individual burden of currently known cardiovascular risk factors is not the only determinant of endothelial function; rather endothelial integrity depends on the  balance of all cardiovascular risk factors and vasculoprotective elements in a given individual, including the genetic predisposition. Recent studies have demonstrated that patients with endothelial dysfunction have an increased risk of clinical cardiovascular events. The coronary events including myocardial infarction, death or neovascularization occur only in patients with severely impaired endothelial functions. Interventions like risk factor modification and treatment with various drugs may improve prognosis. Hence given its reversibility and granted the availability of a diagnostic tool to identify  patients at risk and to control the efficacy of therapy in clinical practice, endothelial dysfunction may be an attractive target, in an effort to optimize individualized strategies to reduce cardiovascular morbidity and mortality. Thus a deep insight in to the pathophysiology of endothelium and its functions can be of value in identifying and  preventing the risk factors of various cardio vascular diseases. The early risk prediction would ensure a better quality of life in the adulthood if the preventive steps are taken in the childhood itself since there is no age bar for the onset of the endothelial dysfunction. KEY WORDS: Endothelial dysfunction; Atherosclerosis; Cardiovascular events; Risk factor; Prognosis INTRODUCTION Endothelium is an inert lining of the blood vessels, but is highly specialized, metabolically active interface between blood and the underlying tissues. The endothelium plays a vital role in vascular homeostasis, vascular tone regulation, vascular smooth cell proliferation, trans endothelial leukocyte migration, thrombosis and thrombolytic balance. In response to various mechanical and chemical stimuli, endothelial cells synthesize and release a large number of vasoactive substances, growth modulators and other factors that mediate these functions. Endothelial dysfunction can be defined as, “the  partial or complete loss of balance between vasoconstrictors and vasodilators, growth  promoting and growth inhibiting factors,  proatherogenic and anti-atherogenic factors” 1 . Endothelial dysfunction is now regarded as an early pivotal event in atherogenesis 2  and has  been shown to precede development of clinically detectable atherosclerotic plaques in the coronary arteries 3 . It has also been considered an important event in the development of micro vascular complications in diabetes 4 .  ( Corresponding Author:   Dr. Namrata Chhabra Additional Professor, Department of Biochemistry, S.S.R. Medical College, Mauritius, Email: namarta28@hotmail.com)   Internet Journal of Medical Update, Vol. 4, No. 1, January 2009 Review   Copyrighted © by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from http://www.geocities.com/agnihotrimed    34In endothelial dysfunction, there is reduction in the bio-availability of vasodilators, in particular, nitric oxide (NO), whereas endothelial derived contracting factors are increased  5 . On the other hand, endothelial dysfunction, aside from denoting impaired endothelium dependent vasodilatation, also comprises a specific state of ‘Endothelial activation’ which is characterized  by a pro-inflammatory, proliferative and  procoagulatory milieu that favours all stages of atherogenesis ( Figure 1 ) 6 . Given this relationship between endothelial dysfunction and atherosclerosis, it is likely that the status of endothelial function may reflect the propensity of an individual to develop atherosclerotic disease, and thus the presence of endothelial dysfunction may serve as a marker of an unfavorable cardiovascular prognosis 7 . Figure 1: Shows   the central role of endothelial function in the causation and progression of atherosclerosis. Endothelial dysfunction not only denotes impaired endothelial dependent vasodilatation, but also depicts a state of endothelial activation which is characterized by a proinflammatory, proliferative and procoagulatory milieu that favours all stages of atherogenesis. ENDOTHELIAL DYSFUNCTION AND ATHEROSCLEROSIS Recent insight into the basic mechanisms involved in atherogenesis indicate that deleterious alterations of endothelial physiology , also referred to as endothelial dysfunction , represents a key early step in the development of atherosclerosis and are also involved in plaque  progression and the occurrence of atherosclerotic complications 8 . Although the association between cardiovascular risk factors and atherosclerotic disease is well documented, the mechanism by which these risk factors induce lesion formation and lead to events is not entirely defined. Given its strategic location and biological properties, the endothelial cell layer that represents a mechanical and biological barrier between the  blood and the vascular wall and is likely to serve as the ‘missing link’ between any given risk factor and its detrimental vascular effects 9 . Most, if not all risk factors that are related to atherosclerosis and cardiovascular morbidity and mortality, including traditional and nontraditional risk factors, are also found to be associated with endothelial dysfunction. Many of these risk factors, including hyperlipidemia, hypertension, diabetes and smoking are associated with overproduction of reactive oxygen species or increased oxidative stress 10  (Figure   2). By reacting with NO, ROS may reduce vascular NO bioavailability and promote cell damage. Hence increased oxidative stress is considered a major mechanism involved in the  pathogenesis of endothelial dysfunction and may serve as a common pathogenic mechanism of the   Internet Journal of Medical Update, Vol. 4, No. 1, January 2009 Review   Copyrighted © by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from http://www.geocities.com/agnihotrimed    35effect of risk factors on the endothelium 11-13 . Risk to develop endothelial dysfunction increases with the number of risk factors present in an individual but the potential to alter endothelial function may vary between risk factors 14 . Taken together, the status of endothelial function represents an integrated index of both the overall cardiovascular risk factor burden and the sum of all vasculoprotective factors in any given individual 15 . Moreover, given its pivotal role in the atherogenic process, endothelial dysfunction may be regarded as the “ultimate risk of the risk factors” indicating the existence of a specific atherogenic vascular milieu 7  which is associated with perfusion abnormalities and cardioavascular events. Figure 2: Production of nitric oxide (NO) by endothelial cells . NO is produced by the action of endothelial nitric oxide Synthase (eNOS) on L-arginine. This reaction requires a number of cofactors, including tetrahydrobiopterin (BH 4 ) and nicotinamide adenine dinucleotide phosphate (NADPH). Increased intercellular Ca ++  in response to vasodilator agonists or shear stress displaces the inhibitor caveolin from calmodulin (CaM), activating eNOS. NO diffuses to vascular smooth muscle and causes activation of protein kinase which causes phosphorylatiom of k+ dependent channels resulting in relaxation of the smooth muscles.   SUBSTANCES RELEASED BY THE ENDOTHELIUM Endothelium releases a group of substances to maintain the vascular homeostasis. Nitric oxide, Bradykinin, Prostacyclin, Serotonin, Histamin, Substance P and Endothelium- derived hyperpolarizing factor are the vasodilators while the substances like Angiotensin, Endothelin (ET-I), Thromboxane A2, Serotonin, Arachidonic acid, Prostaglandin H2 and Thrombin are the   Internet Journal of Medical Update, Vol. 4, No. 1, January 2009 Review   Copyrighted © by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from http://www.geocities.com/agnihotrimed    36vasoconstrictor molecules released by the endothelium 16 . Platelet derived mediators, such as Serotonin, induce vasoconstriction in the  presence of a dysfunctional endothelium Moreover. Vasoconstrictor response to these stimuli is increased by Endothelin-1 17 ,   concentration of which are elevated in the  plasma of patients with early and advanced atherosclerosis 18   as well as in culprit lesions. A healthy endothelium is characterized by an antithrombotic milieu mediated by the secretion of various factors that exert antiaggregatory effects on platelets (NO and prostacyclin) or have anticoagulatory (heparin and protein/s) or fibrinolytic effects (by tissue plasminogen activator, plasminogen activator inhibitor-1 and thrombomodulin). Endothelium derived NO, Prostcyclins, Bradykinin, Heparin sulfate, transforming growth factor, etc are the inhibitors of the smooth cell growth which tend to balance the effect of the smooth cell growth promoters which are Platelet derived growth factors, Basic fibroblast growth factor, Insulin like growth factor-1, Endothelin and Angiotensin etc . (Table 1) Table 1: Substances released by endothelium Substances Examples Vasodilators  Nitric oxide; Bradykinin; Prostacyclin; Endothelium-derived hyperpolarizing factor; Serotonin; Histamine; Substance P Vasoconstrictors Angiotensin II (AII); Endothelin (ET-1); Thromboxane A2; Serotonin; Arachidonic acid; Prostaglandin H2; Thrombin  Promoters   Platelet derived growth factor (PDGF); Basic fibroblast growth factor (PGF); Insulin-like growth factor – I (IGF-I); Endothelin (ET1); Angiotensin  Inhibitors  Nitric oxide; Prostacyclin; Bradykinin; Heparin sulfate; Transforming growth factor I (TGFB)  Adhesion molecules   Endothelial leukocyte adhesion molecule; Intercellular adhesion molecule (ICAM); Vascular cell adhesion molecule (VCAM) Thrombolytic factors   Tissue-type plasminogen activator; Plasminogen activator inhibitor-1 (PAI-I); Thrombomodulin ROLE OF NITRIC OXIDE The most critical of the substances released by endothelium is nitric oxide (NO) (Table- 1)  which is produced by the conversion of the substrate L-Arginine to L-Citrulline by the enzyme, Nitric oxide Synthase (eNOS) (Figure 2) . NOS is activated, upon stimulation of endothelium by a variety of stimuli including shear stress, substance P and Acetyl choline 8 .  NO thus formed diffuses into the underlying vascular smooth muscles to stimulate the activation of Guanylate cyclase , which in turn converts GTP to the smooth muscle relaxant compound cGMP in the vascular smooth muscle cells 19 . The increase in cGMP leads to activation of cyclic GMP- dependent protein kinase, which in turn leads to phosphorylatiom of potassium dependent channels with consecutive hyper  polarization and extrusion of calcium ions resulting in VSMC (Vascular Smooth Muscle Cell) relaxation 20 .  NO not only produces vasodilatation, but it also  participates in various processes that are  beneficial to the vasculature such as reduction of vascular smooth muscle cell migration and growth , platelet aggregation and thrombosis , monocyte and macrophage adhesion and inflammation (Table1) 21 . In general the substances released by endothelium have important autocrine as well as paracrine functions and help to maintain not only the normal health of vascular wall but also control the haemostatic functions and the hemodynamic  balance of the entire body 22 . ENDOTHELIAL DYSFUNCTION AS CLINICAL SYNDROME The presence of endothelial dysfunction can be regarded as a clinical syndrome that per se is associated with and predicts an increased rate of adverse cardiovascular events 21 . Endothelial dysfunction and acute coronary syndrome: Endothelial dysfunction may play a fundamental role in the pathogenesis of acute coronary syndromes (ACSs); such as unstable angina and acute myocardial infarction 22 .   Endothelial dysfunctions contributes to enhanced  plaque vulnerability owing to reduced anti-inflammatory potential, and favours thrombus   Internet Journal of Medical Update, Vol. 4, No. 1, January 2009 Review   Copyrighted © by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from http://www.geocities.com/agnihotrimed    37formation due to reduction in the anticoagulatory  potential and increase in endothelial production of procoagulatory mediators (e.g. tissue factor and plasminogen activator inhibitor) and thus may be viewed as an important contributory factor for several aspects of ACSs 23 . Various studies have provided evidence for a direct contribution of coronary endothelial dysfunction to myocardial perfusion defects associated with intracoronary administration of acetylcholine in  patients without obstructive CAD 7 .   Endothelial dysfunction and hypertension:  Hypertension is directly implicated in the  pathophysiology of various cardiovascular disease states and is a significant contributor to ill health, leading to an excess of both morbidity and mortality. The etiology of hypertension has  been explored in depth, but the pathophysiology is multifactorial, complex, and poorly understood. Recent interest has been directed toward investigating the purported role of the endothelium, which acts as an important regulator of vascular homeostasis. Endothelial dysfunction is now recognized to occur in hypertension, regardless of whether the etiology is essential or secondary to endocrine or renal  processes 24 . The pathogenesis of systemic sclerosis (SSc) includes vasculopathy with endothelial dysfunction 25 .  Nitric oxide (NO) acts to maintain vascular tone. Reduced bioavailability of NO appears to be the key process through which endothelial dysfunction is manifested in hypertension. The result is of an imbalance of counteracting mechanisms, normally designed to maintain vascular homeostasis, leading to vasoconstriction and impaired vascular function. It has become increasingly apparent that these changes may be effected in response to enhanced oxidative stress,  possibly as a result of systemic and localized inflammatory responses 24 . EVALUATION OF ENDOTHELIAL FUNCTION There is no single and standard test to fully assess the endothelial functions in vivo. Because the endothelium regulates several vascular functions, the assessment of each of them is a  potential way to evaluate its integrity. A common approach to the evaluation of endothelial function is the assessment of blood flow and vascular reactivity since the first description of endothelial dysfunction in atherosclerotic epicardial coronary arteries in 1986 by Ludmer  and colleagues 26 . Invasive assessment of coronary endothelial function by quantitative coronary angiography and coronary Doppler flow measurements, along with graded intracoronary infusions of endothelium dependent vasodilators such as acetylcholine were considered the ‘Gold standard’ for endothelial function testing 27 . However, during the last decade, other less invasive or noninvasive techniques for the assessment of endothelial function including stain gauge forearm plethysmography in conjugation with inta-arterial infusion of endothelium dependent vasodilators such as methacholine or acetylcholine and high resolution external vascular ultrasound to measure flow mediated endothelium dependent dilatation (FMD) of the  brachial artery during reactive hyperemia , have  been developed. These techniques are based on the fact that endothelial dysfunction is not confined to the coronary arteries but rather represents a systemic disorder that also affects vascular beds including both conduit arteries and small resistance vessels in the extremities 28 . Another approach is to measure levels of the members of endothelial activation, such as soluble vascular cell adhesion molecule (VCAM), soluble intracellular adhesion molecules (ICAM), Endothelin-I (ET-I) and other markers of coagulation and fibrinolysis such as PAI-I, Tissue plasminogen activator or Von-Willebrand factors (VWP) and markers of low grade inflammation such as C-reactive  proteins, IL-I, IL-6, and TNF-alpha. 29 The identification and quantification of circulating endothelial cells (CECs) has evolved as a novel marker of endothelial function. As a technique, it correlates with other markers of endothelial function such as flow-mediated dilation, the measurement of von Willebrand factor, and tissue plasminogen activator. Quantification of CECs is difficult due to low numbers, variable morphology, and a lack of standardization in current techniques used. CECs appear to be a different population of cells to endothelial  progenitor cells 30 . (Figure 3)
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