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Atherosclerosis

Atherosclerosis, Coronary Artery Disease and Endothelium

One of the foremost leaders of mortality in the US is coronary artery disease (CAD). This disease strikes many older men and women, as a result from the infamous factors of high cholesterol, high blood pressure, and diabetes mellitus, not to mention others. Thanks to research over the last decade, there is more understanding of the role endothelium plays in the coronary system. Instead of having non-active, diffusional barrier-like qualities, as was once thought, the endothelium serves many critically important functions. At the blood vessel walls, the endothelium synthesizes and releases active substances such as nitric oxide and bradykinin, two potent regulators of vessel function. It is found that the physiologic changes in the endothelium affect the mechanisms responsible for atherosclerosis, and progressively in coronary artery disease. The changes that generate these conditions are known as endothelial dysfunction. As we will see, even the smallest factors can play a widespread role in atherogenesis, or the making of degenerative plaques of cholesterol in the inner layer of an artery. Atherosclerosis, a condition increasing with age, is marked by the deposition of lipids into already-present plaques, causing elevated plaques. The inner layer, or endothelium, is the primary site of development of atherosclerosis.

The endothelium is a "highly dynamic, multifunctional organ whose central role is to respond to changes in stress and blood flow (Jairath, 1999). The endothelium is the largest organ in the body; its total mass is equal to about five human hearts, and surface area about the size of a tennis court. The vascular tone of the blood vessel is maintained by endothelium-released vasoconstrictors and vasodilators. Vasoconstrictors include endothelin, angiotensin II, thromboxane A2, arachidonic acid, prostaglandin H2, thrombin, and nicotine. Vasodilators include nitric oxide, prostacyclin, bradykinin, endothelium-derived hyperpolarizing factor, acetylcholine, serotonin, histamine, and substance P.

The endothelium also regulates vascular cell growth of smooth muscle cells. It does so by producing some of the platelet-derived growth factor that is also made by platelets and macrophages. This factor is released onto receptors of smooth muscle cells, causing proliferation and migration. Circulating macrophages may enter the endothelium and produce thrombin to convert fibrinogen into fibrin. The resulting thrombin-fibrin complex is a strong smooth muscle cell growth stimulus (Sheppard and Davies, 1998). There are also endothelial qualities that prevent smooth muscle cell growth. These are circulating nitric oxide, cyclic GMP, and L-arginine, a precursor of nitric oxide. The endothelium produces L-arginine, and this is converted by nitric oxide synthase into nitric oxide. The nitric oxide released into the lumen binds to cGMP, and concentration of cGMP increases, to inhibit smooth muscle cell proliferation.

Endothelin and angiotensin II are the strongest vasoconstrictors. Angiotenin II acts directly by being actively transported through the epithelium and into the abluminal space, where it reacts with multiple smooth muscle cell receptors (Pepine et al, 1997). Endothelin is derived within the endothelium. Along with direct reaction onto a smooth muscle cell receptor, endothelin is feed-forward stimulated by angiotensin II. On the reverse side, endothelium houses nitric oxide, the powerful vasorelaxer. To function, nitric oxide production is stimulated by receptors on the endothelium responding to physical stimuli, such as shear stress, or physiologic stimuli such as bradykinin and acetylcholine. Nitric oxide travels into the smooth muscle cells, where it elevates the level of cyclic GMP, which relaxes the muscle. Also within the endothelium, nitric oxide indirectly increases the function of both prostacyclin and endothelium-derived hyperpolarizing factor. Prostacyclin is transported into the smooth muscle cell and raises the level of cyclic AMP to relax the cell, while endothelium-derived hyperpolarizing factor opens more potassium channels in the smooth muscle cell membrane (Pepine et al, 1997).

Angiotensin II and bradykinin are controlled by angiotensin-converting enzyme, which is locally produced in the endothelium. Angiotensin-converting enzyme activates angiotensin II by direct conversion of angiotensin I. When this conversion happens, angiotensin-converting enzyme degrades bradykinin. The direct actions of angiotensin II are receptor-mediated smooth muscle cell contraction and proliferation, and enhancing superoxide anion formation, used to degrade nitric oxide and activate monocytes to bind to the endothelium. Bradykinin is locally produced by the endothelium and responds to blood flow. Bradykinin has important inhibitory qualities including he release of nitric oxide, by acting on endogenous receptors that activate the L-arginine to nitric oxide reaction. When angiotensin-converting enzyme is inhibited by such things as angiotensin-converting enzyme inhibitors, this allows bradykinin to accumulate and increase its actions in a cascade effect (Pepine et al, 1997).

The endothelium’s next main duty is to regulate antithrombotic mechanisms, fibrinolysis, and anticoagulation. The cells synthesize a glycosaminoglycan that binds to antithrombin III, which inactivates the coagulation proteases such as thrombin and factor X (Pepine et al, 1997). The endothelium produces thrombomodulin to bind to thrombin and convert this to an activator of protein C. Protein C will inactivate the thrombus formers, factors Va and VIIIa. Platelet activation is inhibited by endothelium-derived prostacyclin through an unclear mechanism. Another inhibitor of platelet aggregation is when endothelial cells convert platelet-derived endoperoxidases to prostacyclin (Pepine et al, 1997).

Fibrinolysis is important in the tissue repair and clot dissolution of vessel walls (Fuster et al, 1996). Controlling the balance of fibrin degradation are tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Stimuli such as shear stress, venous occlusion, thrombin, bradykinin, and cytokines are all positive activators of t-PA. T-PA will then convert plasminogen to plasmin, and plasmin degrades fibrin to stop clotting. PAI-1 is synthesized by platelets and in the endothelium via angiotensin II. PAI-1 is selected for by the conversion of angiotensin II into angiotensin IV. This protein acts on a receptor that may express PAI-1, and PAI-1 may in turn lead to thrombosis (Pepine et al, 1997). Oxidized lipoproteins native to and encompassing endothelium causes more synthesis of PAI-1, perhaps by the indirect recruitment of monocytes to the site of oxidized lipoproteins, causing platelet adhesion to the endothelial surface and their subsequent production of PAI-1

A normal endothelium will usually inhibit vascular smooth muscle cell growth. It will also inhibit platelet and leukocyte adhesion, aggregation, and thrombosis. Different factors will tamper with this regular function, and are explained later. Vasoconstriction occurs as a result of such factors, because decreased blood flow is needed to accommodate injury and dysfunction. In the coronary arteries disease patients, the level of dysfunction is scattered with areas of severe to areas of low dysfunction (Pepine et al, 1997). This suggests that repair is possible in the coronary endothelium. The main idea found was that nitric oxide release is the determinant for whether or not endothelium dysfunction is present. Also important to note is that while nitric oxide and all vasoconstrictors have the opposing effects, releasing excess amounts of vasoconstrictors is not shown to reduce the degree of effect of nitric oxide (Pepine et al, 1997). This infers that nitric oxide’s role is a powerful influence on the maintenance of endothelium. We will see how nitric oxide is responsible in the formation of atherosclerosis, after pointing out the risk factors that lead to atherogenesis.

There are a multitude of factors established that are highly related to endothelial dysfunction. The first of these is hypertension, which is signified by a reduced vasodilation response to acetylcholine and reduced synthesis of nitric oxide. It is not clear though if hypertension is caused by endothelial dysfunction. Hypercholesterolemia is a huge risk factor that is known to impair acetylcholine response. It is known that endothelium-derived nitric oxide modulates the expression of adhesion molecules on the endothelium, thereby enhancing the adhesiveness for monocytes, which take up low-density lipoproteins. The amount of low-density lipoproteins also increases the chance for oxidation, and that carries the negative effects of inhibiting vasodilation, growth factor stimulation, and cytokine production (Pepine et al, 1997). Smoking leads to dysfunction since nicotine is proposed to enhance platelet-vessel wall binding, reduce prostacyclin, increase circulating and endogenous low-density lipoproteins, and increase oxidation by superoxide anion (Pepine et al, 1997). Diabetes is yet another factor, where the nitric oxide production pathway is decreased, and the release of vasoconstrictors is increased. Postmenopausal women also are at a high risk, as low estrogen levels are associated with endothelium-dependent vasoconstriction. Stress, depression, and anxiety too are factors because of the higher parasympathetic autonomic nervous system actions, which vasoconstrict the vasculature. Finally, genetic predisposition increases risk due to the level of gene protein homocysteine. The higher the severity of atherosclerosis, the higher the level of homocysteine levels (Pepine et al, 1997). Endothelial cell responses to homocysteine include injury, platelet-endothelial cell interactions, and thrombomodulin expression leading to thrombogenesis.

The mechanism for atherogenesis is not surely known because of varying evidence of how superoxide anion affects the endothelium. In a simple view, atherogenesis is caused by the immune system response upon the endothelium to the various risk factors. To any degree, these factors all decrease nitric oxide activity. That effect will induce three types of endothelial cell adhesion molecules to be expressed, the most important being vascular cell adhesion molecule-1. A chemoattractant is released and recruits monocytes from the circulation. The monocytes adhere to the endothelium by adhesion cytokines. Low-density lipoproteins—present in practically all individuals’ endothelium of the developed world—freely move in and out of the tunica intima. The endothelium and smooth muscle cells produce superoxide anions, or oxygen free radicals. The anions invoke the monocytes to migrate into the intima, as well as promote more monocyte adhesion to the endothelium (Sheppard & Davies, 1998). The monocytes in the intima convert into macrophages, and do nothing until the next critical step. A small portion of the lipids within the intima is oxidized by the superoxide anions. The macrophages’ scavenger receptors take up some of this lipid. Because the receptors do not down-regulate, lipid uptake continues and transforms the macrophages into foam cells (Sheppard & Davies, 1998). The foam cells lie in the intima and form the lesion of the endothelium. When death of the foam cell occurs, the lipids inside move out and form the lipid core of an atheroma. Continual lipid deposition, smooth muscle proliferation, and nitric oxide inhibition forms later stages of atherosclerosis.

The role of cardiovascular endothelium is of much greater importance than was thought ten years ago. It is a crucial organ to maintain vascular tone and structure, as well as make clotting factors, and mediates the immune response. Applying this to the complex nature of coronary artery disease requires knowledge of a vast and immensely dynamic amount of contributors. One of the fundamental players preventing coronary artery disease is nitric oxide, constantly providing antiatherogenic effects upon the endothelium. The fundamental antagonists such as hypertension, hypercholesterolemia, smoking, and diabetes, all block nitric oxide’s influences while introducing counter effects. For CAD to be avoided in most people, cardiovascular endothelium needs benefits from antiproliferation, antiatherogenesis, antithrombosis, and vasodilation. Indeed, many drugs exist today that are reaped of their benefits. Yet this should combined with diet and lifestyle changes such as smoking cessation and exercise, eating foods with antioxidants, consuming lipid-lowering agents, and in women, consuming estrogen.

Bibliography:

2. Jairath, Nalini. Coronary Heart Disease & Risk Factor Management: A Nursing Perspective. W.B. Saunders Co: Philadelphia, 1999.

3. Pepine, Carl J. et al. "Endothelial Function in Cardiovascular Health and Disease." Monograph. Landmark Programs: New York, NY, 1997.

4. Sheppard, Mary and Michael J. Davies. Practical Cardiovascular Pathology. Oxford University Press, Inc: New York, NY, 1998.



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