Medicine/7. Clinical medicine

Parakhonsky A.P.

Kuban medical institute, Medical center "Health", Krasnodar, Russia

Mechanism of immune inflammation - the basis of the way

of treatment of atherosclerosis

Atherosclerosis, a chronic inflammatory disease of the arterial wall, is the major cause of morbidity and mortality from Cardiovascular Disease (CVD) in much of the world’s population. The disease involves the formation of Plaques in arterial walls that narrow the arterial passage, restricting blood flow and increasing the risk of occlusion of blood flow by a myocardial infarction. There is now a consensus that Atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The Oxidative Modification hypothesis predicts Low-Density Lipoproteins (LDL) oxidation as an early event in Atherosclerosis, and oxidized LDL as one of the important contributors of Atherogenesis. Lipoproteins are water-soluble spherical particles that transport nonpolar lipids. In humans, LDLs are the major Cholesterol transporters and consist of a hydrophobic core containing Cholesteryl ester molecules, Triacylglycerols; and a surface monolayer of polar lipids (primarily Phospholipids) and Apolipoprotein-B (ApoB) [1]. LDL is commonly referred to as “Bad Cholesterol” due to its role in promoting Atherosclerosis. Oxidation of LDL in the Artery wall is one of the major physiologically relevant mechanisms for the pathogenesis of Atherosclerosis. LDL in the plasma originates from very-Low Density Lipoprotein (vLDL) produced by the liver. vLDL is converted to LDL by the action of Lipoprotein Lipase (LPL), an enzyme that hydrolyzes triglycerides in vLDL, removing them from the vLDL particle and releasing free fatty acids. The removal of triglycerides from vLDL by LPL leaves a greater proportion of Cholesterol, increasing the density of the particle and changing it to LDL. One of the first steps in the development of Atherosclerosis is the passage of LDL out of the Arterial lumen into the Arterial wall. Plasma LDL is transported across the intact Endothelium and becomes trapped in the Extracellular Matrix (ECM) of the subendothelial space where it is subjected to oxidative modifications to produce highly oxidized and aggregated LDL, referred to as Oxidized LDL (OxLDL). OxLDLs are believed to be the most Atherogenic forms of LDL. Various cellular and biochemical mediators: Reactive Oxygen Species (ROS), the enzymes Sphingomyelinase (SMase), Secretory Phospholipase-2 (sPLA2), other Lipases, and Myeloperoxidase (MPO), have been proposed to initiate and regulate LDL oxidation and aggregation. The various components in OxLDL include Lipid Hydroperoxides, Oxysterols, Lysophosphatidylcholine, and Aldehydes [2]. OxLDL is a potent inducer of inflammatory molecules. It stimulates inflammatory signaling by Endothelial cells, releasing chemotactic proteins such as Monocyte Chemotactic Protein-1 (MCP1) and growth factors such as Monocyte Colony Stimulating Factor (mCSF), which help in the recruitment of Monocytes into the Arterial wall [1]. OxLDLs also promote the differentiation of Monocytes into Macrophages that take-up the oxidized LDL in a process that converts them into Foam cells, the hallmark cell of Atherosclerosis. Apart from that, OxLDL also has other effects, such as inhibiting the production of Nitric Oxide (NO), an important mediator of vasodilation and expression of endothelial leukocyte adhesion molecules. The oxLDL particles are recognized by Macrophage Scavenger Receptors: Scavenger Receptor-A (SR-A), CD36 Antigen (CD36) and Macrophage Antigen CD68 (CD68). The Macrophages take up the OxLDLs, become enlarged and full of lipid. These cells accumulate in tissue and are transformed into lipid-laden Foam cells, dying and forming part of the Atherogenic Plaque (Atherosclerotic Plaque) in the fatty streak lesions. Activated Macrophages express a range of cytokines (Tumor Necrosis Factor-α (TNFα), Interleukin-1β (IL-1β), Macrophage Inflammatory Protein-1α (MIP1α)), which stimulate endothelial cells to express adhesion proteins (Vascular-Cell-Adhesion Molecule-1 (VCAM1), Intracellular-Adhesion Molecule-1 (ICAM1) etc). This facilitates the process of binding of additional blood Monocytes to the Endothelium and their recruitment into the Intima. The cytokines released from the Macrophages and Foam cells also stimulate the SMCs to migrate into the Intima, then proliferate and secrete Collagen, Elastin and Proteoglycans to form a fibrous matrix. This results in the formation of Plaques with fibrous caps. The mature Atherosclerotic Plaque consists of a fibrous cap - comprising variable numbers of SMCs, foamy Macrophages, Lymphocytes, Extracellular-Matrix and a variety of Inflammatory Mediators - which encapsulates an acellular, lipid-rich necrotic core that is derived, in part, from dead Foam cells. The mature Plaques protrude into the Arterial lumen, and cause obstruction of Arterial blood flow. Although advanced lesions can impede blood flow, Myocardial Infarctions and strokes result from an acute occlusion that is due to the formation of a Thrombus, which forms in response to rupture or erosion of the Plaques. Among various factors that may destabilize Plaques and promote Thrombosis are infection, which may have systemic effects such as induction of Acute Phase Proteins and local effects such as increased expression of Tissue Factor (TF) and decreased expression of Plasminogen Activator (PA). Numerous physiologic triggers: Physical exertion, mechanical stress due to an increase in Cardiac contractility, Pulse Rate, Blood Pressure and possibly, Vasoconstriction initiate the rupture of a vulnerable Plaque. Rupture leads to the activation, adhesion, and aggregation of Platelets and the activation of the Clotting Cascade, resulting in the formation of an occlusive Thrombus (Clot). Thrombus formation in the lumen of a Coronary Artery may lead to its partial blockage of blood flow, or, can result in Myocardial Infarction [1]. Atherosclerosis is an inflammatory disorder initiated by an accumulation and subsequent oxidation of LDL in the arterial Intima. Thus, therapeutic intervention in atherosclerosis should focus either on lowering plasma LDL levels through diet and medication, or blocking LDL oxidation. The Statins are drugs commonly used to block cholesterol production and increase the expression of the LDL Receptor (LDLR) by the liver cells, removing LDL from circulation [4]. Nicotinic acid, Clofibrate, Lovastatin, Pravastatin, Atorvastatin are some of these drugs. Antioxidants such as High Density Lipoproteins (HDLs) and Vitamin-E are potential Antiatherogenic agents as they can inhibit LDL oxidation. Most attention has focused on Vitamin-E, as it is the major lipid-soluble antioxidant in LDL. In addition to the inhibition of oxidative modification of LDL, Vitamin-E has been identified recently as a favorable modulator of other Atherogenic processes at the molecular and cellular levels.

References:

1. Catapano A.L., Maggi F.M., Tragni E. Low density lipoprotein oxidation, antioxidants, and atherosclerosis // Curr. Opin Cardiol. – 2000. – V. 15, N. 5. P. 355-363.

2. Perrin-Cocon L., Coutant F., Agaugue S., Deforges S., Andre P., Lotteau V. Oxidized low-density lipoprotein promotes mature dendritic cell transition from differentiating monocyte // J. Immunol. – 2001. – V. 167, N. 1. – P. 3785-3791.

3. Norata G.D., Pirillo A, Catapano A.L. Statins and oxidative stress during atherogenesis // J. Cardiovasc. Risk. - 2003. – V. 10, N. 3. – P.181-189.