**1. Introduction**

Cardiovascular diseases (CVDs) remain the leading cause of death in modern societies. The primary cause of dramatic clinical events of CVDs, such as unstable angina, myocardial in‐ farction and stroke, is the atherosclerotic process [1,2,3].

The pathophysiological mechanisms of atherosclerosis are complicated and the integrated picture of the disease process is not yet complete, so currently is largely investigated. It is widely recognized that oxidative stress, lipid deposition, inflammation, Vascular smooth muscle cells (VSMCs) differentiation and endothelial dysfunction play a critical role in the formation, progression and eventually rupture of the atherosclerotic plaque [4]. Multiple risk factors have been associated with the development of atherosclerotic lesions; these include diabetes mellitus, hypertension, obesity and tobacco smoking. The risk factors are influenced by genetic predisposition, but also by environmental factors, particularly diet. Moreover, ag‐ ing promotes physiological changes, such as oxidative stress, inflammation and endothelial dysfunction strictly associated with the pathophysiology of atherosclerosis [5].

The common belief that signs of atherosclerosis and CVDs are clinically relevant only dur‐ ing adult and elderly age is gradually changing, increasing evidence supports that athero‐ genesis is initiated in childhood [6].

Low-density lipoproteins (LDL) are crucial to the development of atherosclerotic lesions, whereas high-density lipoproteins (HDL) are inhibitors of the process, primarily through the process of reverse cholesterol transport [4,7]. Dysfunctional lipid homeostasis plays a central role in the initiation and progression of atherosclerotic lesions. Oxidized-LDL (ox-LDL) induces endothelial dysfunction with focal inflammation which causes increased ex‐ pression of atherogenic signaling molecules that promote the adhesion of monocytes and T

© 2013 Fabrizio Rodella and Favero; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

lymphocytes to the arterial endothelium and their penetration into the intima. Early stages of plaque development involve endothelial activation induced by inflammatory cytokines, ox-LDL and/or changes in endothelial shear stress [8,9]. The monocyte-derived macrophag‐ es, by taking up ox-LDL, become foam cells, which are typical cellular elements of the fatty streak, the earliest detectable atherosclerotic lesion [10].

**2. Atherosclerosis and oxidative stress**

pholipids, F2α-isoprostanes and oxysterols [15].

plays a pivotal role in the atherogenesis [16].

**Figure 2.** Generation and main damages induced by ROS. Modified from [17]. O2

ROS may contribute to LDL oxidation, inflammation, local monocyte chemoattractant pro‐ tein production, upregulation of adhesion molecules and macrophages recruitment, endo‐ thelial dysfunction, platelet aggregation, extracellular matrix remodelling through collagen degradation, thus playing a central role in the development and progression of atheroscle‐ rosis and eventually in plaque rupture [17,18,19]. Several oxidative systems potentially contribute to LDL oxidation *in vivo*, included NADPH oxidases, xanthine oxidase, myelo‐

hydrogen peroxide..


: superoxide; HO`: hydroxyl; H2O2:

Oxidative stress is defined as an imbalance between pro-oxidant and anti-oxidant factors in favour of pro-oxidants and is central to the pathophysiology of atherosclerosis. The analysis of plaque composition has revealed products of protein and lipid oxidation, such as chlori‐ nated, nitrated amino acids, lipid hydroperoxides, short-chain aldehydes, oxidized phos‐

Atherosclerosis and Current Anti-Oxidant Strategies for Atheroprotection

http://dx.doi.org/10.5772/53035

3

Excessive production of reactive oxygen species (ROS) during oxidative stress, out stripping endogenous anti-oxidant defence mechanisms, has been implicated in processes in which they oxidize and damage DNA, protein, carbohydrates and lipids. There are multiple poten‐ tial enzymatic sources of ROS, including mitochondrial respiratory cycle, heme, arachidonic acid enzyme, xanthine oxidase, nitric oxide synthese and others. However, the predominant ROS-producing enzyme in the VSMCs and in the myocardium is NADPH oxidase, that

After initial injury, different cell types, including endothelial cells, platelets and inflammato‐ ry cells release growth factors and cytokines that induce multiple effects: oxidative stress, inflammation, VSMCs differentiation from the contractile state to the active synthetic state and then proliferate and migrate in the subendothelial space [11,12]. Inflammatory cell accu‐ mulation, migration and proliferation of VSMCs, as well as the formation of fibrous tissue, lead to the enlargement and restructuring of the lesion, with the formation of an evident fi‐ brous cap and other vascular morphological changes [2,13]. Atherosclerotic plaques result from the progressive accumulation of cholesterol and lipids in oxidized forms, extracellular matrix material and inflammatory cells [14]. In fact, atherosclerosis manifests itself histologi‐ cally as an arterial lesions known as plaques, which have been extensively characterized: plaques contain a central lipid core that is most often hypocellular and may include crystals of cholesterol that have formed in the foam cells. The lipid core is separated from the arterial lumen by a fibrous cap and myeloproliferative tissue that consists of extracellular matrix and VSMCs. Advanced lesions can grow sufficiently large to block blood flow and so devel‐ op an acute occlusion due to the formation of thrombus or blood clot resulting in the impor‐ tant and severe cardiovascular clinical events [2,10].

**Figure 1.** Main vascular alterations observed during atherogenesis. LDL: low density lipoprotein; HDL: high density lip‐ oprotein.
