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Role of free Radicals


The formation of ROS, such as superoxide anion radical O2- or peroxynitrite ONOO- is postulated to be derived from different cellular sources in the vasculature and in parenchymatous tissues, as also shown in a variety of pathological conditions such as ischemia-reperfusion injury, diabetes, neuro-degenerative processes and during acute and chronic inflammatory responses. Hyperlipidemia with or without atherosclerosis is one of the major metabolic/cardiovascular disease states in which the enhanced formation of ROS is of pivotal pathogenetic importance. The therapeutic or experimental efficacy of various antioxidant substances (such as vitamins, antioxidant enzymes/metabolites) to restore an appropriate extracellular and intracellular redox balance provides further support to the importance of augmented ROS formation in these states. In hypercholesterolemia, these effects on vascular enzyme activities lead to pronounced vasomotor dysfunction (e.g., reduced vasodilator responses).

The detrimental effects of enhanced oxidant stress result largely from the concomitant dysfunction of endogenous nitric oxide (NO) production. This resulting in inactivation of endogenous NO by oxygen-derived radicals (eliciting the formation of the cyto- and genotoxic ONOO - ) or altered function of nitric oxide synthases (NOS) with co-production of O2- . Excessive formation of ONOO- is associated with significant decreases of cellular glutathione content and subsequently of NOS as well as of soluble guanylate cyclase (sGC) activity (e.g., through oxidation of thiol (SH) groups). A dysfunctional NOS, as well as altered enzymatic activities of superoxide dismutase (SOD) with enhanced formation of hydrogen peroxide (H2O2), may be implicated in the excessive ROS formation under different pathophysiological conditions. ROS are also associated with the formation of oxidized LDL that, in turn, stimulates release of ROS and enhanced adhesion molecule expression as well as platelet activity with pro-atherogenic effects in the vasculature. Altered lipid metabolism is closely related to an imbalance of the pro-oxidant/antioxidant metabolic state, as demonstrated in hypercholesterolemic conditions in the presence or absence of atherosclerosis, cardiovascular dysfunction, and inflammatory processes in the vasculature or in parenchymatous tissues. As a net effect, total antioxidant capacity and anti-lipoperoxidation potential seem to be decreased in hyperlipidemia with or without atherosclerosis. It has now become possible to accurately quantify the in vivo and ex vivo concentration of ROS under different (patho) physiological and experimental conditions by electron spin resonance using a new spin probes.

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