Oxidative stress, inflammation and endothelial dysfunction: implications in atherosclerosis. Note II.

Abstract

NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase), with its generically termed NOX isoforms, is the major source of ROS (reactive oxigen species) in biological systems. The oxidant/ antioxidant imbalance in favor of oxidants in the vascular system generates ROS via activation of NADPH oxidase. ROS are small oxygen-derived molecules with an important role in various biological processes (physiological or pathological). Some processes are beneficial and necessary for life under physiological conditions, but they are noxious, harmful under pathophysiological conditions. NADPH oxidases are present in phagocytes and in a wide variety of nonphagocytic cells. The enzyme generates superoxide by transferring electrons from NADPH inside the cell across the membrane and coupling them to molecular oxygen to produce superoxide anion, a reactive free-radical. Structurally, NADPH oxidase is a multicomponent enzyme which includes two integral membrane proteins, glycoprotein gp91phox and adaptor protein p22phox, which together form the heterodimeric flavocytochrome b558 that constitutes the core of the enzyme. During the resting state, the multidomain regulatory subunits p40phox, p47phox, p67phox are located in the cytosol organized as a complex. The activation of phagocytic NADPH oxidase occurs through a complex series of protein interactions. The increased production of free radicals under pathophysiological conditions is an integral part of the production of cardiovascular diseases and in particular of atherosclerosis. At the onset and progression of atherosclerosis, various non-traditional intercorrelated risk factors contribute such as oxidative stress, inflammation and endothelial dysfunction. Oxidative stress plays a crucial role not only in the formation but also in the evolution and destabilization of lesions. Oxidative stress is closely linked to endothelial damage. Endothelium modulates vascular tone by releasing specific vasoactive substances. At the onset and progression of atherosclerosis contributes to decreasing the bioavailability of NO (nitric oxide) or EDRF (endothelium-derived relaxing factor) with an important role in conserving vasodilation and inhibiting vasoconstriction. Clinical and paraclinical investigations show that inflammatory reactions operate at all stages of atherosclerotic events. According to the theory of oxidative stress, atherosclerosis is also the result of the particularly oxidative changes of LDL (low density lipoproteins) in the arterial wall. Excess ROS can produce peroxinitrite with NO, the cytotoxic oxidant important mediator of LDL oxidation with proaterogenic action.