**2. Atherosclerosis and oxidative stress**

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

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‐

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

streak, the earliest detectable atherosclerotic lesion [10].

2 Current Trends in Atherogenesis

tant and severe cardiovascular clinical events [2,10].

oprotein.

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‐ pholipids, F2α-isoprostanes and oxysterols [15].

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 plays a pivotal role in the atherogenesis [16].

**Figure 2.** Generation and main damages induced by ROS. Modified from [17]. O2 - : superoxide; HO`: hydroxyl; H2O2: hydrogen peroxide..

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‐ peroxidase, uncoupled nitric oxide synthase, lipoxygenases and mitochondrial electron transport chain [20,21,22]. Ox-LDL particles exhibit multiple atherogenic properties, which include uptake and accumulation of macrophages, as well as pro-inflammatory, immuno‐ genic, apoptotic and cytotoxic activities, induction of the expression of adhesion molecules on endothelial cells, promotion of monocyte differentiation into macrophages, production and release of pro-inflammatory cytokines and chemokines from macrophages [14].

**3. Atheroprotective strategies**

Recently, various pharmacological therapies have been designed to reduce the development and progression of the atherosclerotic plaque and remarkable therapeutic advances in the treatment of CVDs have been made with insulin sensitizers, statins, inhibitors of the reninangiotensin system and anti-platelet agents [19,26]. However, strictly control of cardiovascu‐ lar risk factors are often difficult to obtain and the progression of atherosclerosis has not been completely prevented with current pharmacological therapeutic options. Moreover, the modern evolution of Western societies seemingly steers populations towards a profound sedentary lifestyle and incorrect diet is becoming difficult to reverse. Understanding of the mechanisms that explain the fatal effects of physical inactivity and incorrect diet, the benefi‐

Atherosclerosis and Current Anti-Oxidant Strategies for Atheroprotection

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

5

Concerning atherosclerosis prevention by foods, dietary supplements and healthy life style may provide prevention and/or treatment to the onset and development of atherosclerosis. Development of an atheroprotective strategy acting on oxidative stress involved in the pathogenesis of atherosclerosis and with little toxicity or adverse effects may provide an ide‐ al therapeutic treatment for atherosclerosis. Actually, numerous studies have investigated the prevention and treatment of atherosclerosis using naturally-occurring anti-oxidants.

In this review we summarize the many pieces of the puzzle to identified molecular targets for prevention and therapy against atherosclerosis and present that a healthy life style has

**Figure 4.** Potential atheroprotective role of anti-oxidants in the atherogenic process. Modified from [27]. ox-LDL: oxi‐

dized-low density lipoprotein; ROS: reactive oxygen species.

natural anti-atherogenic activity which has been forgotten by modern societies.

cial effects of an healthy lifestyle remains largely unexplored [3].

In particular, at endothelial level, ROS regulates numerous signaling pathways including those regulating growth, proliferation, inflammatory responses of endothelial cells, barrier function and vascular remodeling; while at VSMC level, ROS mediates growth, migration, matrix regulation, inflammation and contraction [23,24,25], all are critical factors in the pro‐ gression and complication of atherosclerosis.

A vicious cycle between oxidative stress and oxidative stress-induced atherosclerosis leads to the development and progression of atherosclerosis.

**Figure 3.** Role of ROS and oxidative stress in the atherosclerosis. Modified from [24]. O2: oxygen; O2 - : superoxide; H2O2: hydrogen peroxide; VSMC: vascular smooth muscle cell.
