Oxidative stress, F2-isoprostanes and endothelial dysfunction in hypercholesterolemia

See article by Wilson et al. [9] (pages 601–607) in this issue. Hypercholesterolemia is reported to be associated both with enhanced oxidative stress, related to increased lipid peroxidation [1], and with augmented susceptibility to coronary vasoconstriction [2]. The abnormal coronary vasoreactivity is mainly attributed to endothelial dysfunction, which in hypercholesterolemic man has been demonstrated by several approaches, including coronary and forearm blood flow response to acetylcholine (ACh) [3,4], and flow-mediated dilation [5]. An increased generation of oxidized LDL is a major factor responsible for the vascular damage related to high cholesterol levels, and oxidative stress leads to increased breakdown and/or reduced bioavailability of NO in a number of experimental and clinical models [6]. F2-Isoprostanes, namely 8-epi-prostaglandin F2α (8-epi-PGF2α), have been recently proposed as reliable markers of oxidative stress in vivo [7,8]. Wilson et al. [9] in their study demonstrate that 8-epi-PGF2α causes a dose-dependent vasoconstriction in vitro, in pig coronary strips obtained from normal and hypercholesterolemic animals. Coronary vasoconstriction induced by 8-epi-PGF2α is shown to be modulated by endothelial NO, being increased after both endothelial denudation and L-NMMA administration in control animals. Hypercholesterolemic vessels (HV), in turn, show an increased coronary vasoconstriction to 8-epi-PGF2α which is comparable to that observed in normal animals following endothelium denudation, specific for 8-epi-PGF2α, not being found with other vasoconstrictor prostanoids, and is attenuated by pretreatment with l-arginine or the NO donor NOR-3. These observations suggest a tonic vasoconstrictor activity dynamically opposed by NO, with the net vasomotor effect resulting from the balance of the two systems.