Читать книгу Interventional Cardiology - Группа авторов - Страница 22

Since the 1950s, oxidative stress has a significant role in the pathogenesis of atherosclerosis, and the degree of oxidation correlates with the severity of the diseases [44]. Multiple reactive oxygen species (ROS) generator are present in the vascular wall, including the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, uncoupled endothelial nitric oxide synthase (eNOS), mitochondrial enzymes, and xanthine oxidase (XO), which develops a cross‐talk between the enzymes, creating a vicious cycle [5]. The function of the NADPH oxidase enzymes is to catalyse the one‐electron transfer from NADPH to molecular oxygen, thereby generating ROS [45] in a regulated way in response to, e.g. calcium, growth factors, and cytokines [46]. Seven isoforms of the catalytic, membrane‐spanning NADPH oxidase subunit NOX exist, each encoded by a separate gene, i.e. NOX1–5 and Duox1 and Duox2 [47]. They differ in molecular composition, subcellular localisation, tissue distribution, and expression [48]. Endothelial cells mainly express NOX2 and NOX4, and vascular smooth muscle cells mainly express NOX4 [49]. In vascular smooth muscle cells of resistance arteries, NOX2 expression is relatively high [50], and cardiomyocytes mainly express NOX2 and NOX4 [51], NOX activity contributes to the oxidised LDL production in macrophages [52], overexpression of endothelial adhesion molecules, monocyte infiltration, and VSMC proliferation [53]. Coupled eNOS (the physiological condition) generates NO, which induces vascular smooth muscle relaxation and inhibits platelet aggregation and adhesion [54]. However, under conditions of oxidative stress, eNOS becomes uncoupled, dysfunctional, and generates superoxide instead of NO. Subsequently, low NO bioavailability can up‐regulate VCAM‐1 in the endothelial cell layer that binds monocytes and lymphocytes in the first step of invasion of the vascular wall, via induction of NFkB expression [55]. Furthermore, NO inhibits leukocyte adhesion [56] and NO reduction results in induction of monocyte chemotactic protein‐1 (MCP‐1) expression which recruits monocytes [57]. NO is in a sensitive balance with endothelin1 (ET‐1) regulating vascular tone [58]. Plasma ET‐1 concentrations are increased in patients with advanced atherosclerosis and correlate with the severity of the disease [59,60]. In addition to its vasoconstrictor activity, ET‐1 also promotes leukocyte adhesion [61] and thrombus formation [62]. The deficiency of eNOS cofactor tetrahydrobiopterin (BH4), or eNOS substrate ι‐arginine, or eNOS S‐glutathionylation were found to be the culprit of the eNOS uncoupling [6].3 Endothelial NOS‐dependent ROS production has been shown as one of significant contributor in patients with atherosclerosis [64], hypertension [65], hypercholesterolemia [66], diabetes mellitus [67], and chronic smoker [68].

Mitochondrial is a crucial element in physiology vascular cell growth and function; however, mitochondrial dysfunction can result in excessive ROS production. Mitochondrial oxidative stress also found to be associated with atherosclerosis which can occur under pathological situation because of over ROS production or failure of antioxidant mechanisms [69]. Mitochondrial dysfunction also associated with plaque ruptures, which accelerate the progression of hemodynamically significant atherosclerotic lesions [69], XO is found both in plasma and endothelial cells and generates superoxide anions and hydrogen peroxide by using molecular oxygen as an electron acceptor [70]. The expression and activity of endothelial XO are enhanced in human atherosclerotic plaque [71]. XO stimulates SRs expression on the macrophages and VSMC, namely LOX‐1 and CD 36, resulting in ROS production and subsequently causing transformation of macrophages and VSMC into foam cells [52].