Endothelial cells lipid oxidation products

Enhanced production of vasoconstrictor factors via eicosanoid and/or free radical-related mechanisms has been observed in several cardiovascular disease states. In addition to the well-established role of free radicals in promoting the oxidation of low density lipoprotein cholesterol (LDL-C), changes in free radical status may modify endogenous eicosanoid profiles and/or produce nonenzymatic lipid peroxidation products of the arachidonic acid (AA) cascade such as lipid hydroperoxides and isoprostanes, which have been shown to possess potent vasoactive properties (3). Furthermore, an excess of free radicals may interact with the vascular endothelial cell nitric oxide (NO) to produce highly reactive peroxynitrite radicals, resulting in tissue damage and vasoconstriction (4—6) (Fig. 2). 

Landar, A., Zmijewski, J. W., Dickinson, D. A., Le Goffe, C., Johnson, M. S., Milne, G. L., Zanoni, G., Vidari, G., Morrow, J. D., and Darley-Usmar, V. M. 2006. Interaction of electrophilic lipid oxidation products with mitochondria in endothelial cells and formation of reactive oxygen species. 290, HI777-87. 

High antioxidative activity carvedilol has been shown in isolated rat heart mitochondria [297] and in the protection against myocardial injury in postischemic rat hearts [281]. Carvedilol also preserved tissue GSL content and diminished peroxynitrite-induced tissue injury in hypercholesterolemic rabbits [298]. Habon et al. [299] showed that carvedilol significantly decreased the ischemia-reperfusion-stimulated free radical formation and lipid peroxidation in rat hearts. Very small I50 values have been obtained for the metabolite of carvedilol SB 211475 in the iron-ascorbate-initiated lipid peroxidation of brain homogenate (0.28 pmol D1), mouse macrophage-stimulated LDL oxidation (0.043 pmol I 1), the hydroxyl-initiated lipid peroxidation of bovine pulmonary artery endothelial cells (0.15 pmol U1), the cell damage measured by LDL release (0.16 pmol l-1), and the promotion of cell survival (0.13 pmol l-1) [300]. SB 211475 also inhibited superoxide production by PMA-stimulated human neutrophils. 

Sevanian, A., Hodis, H.N., Hwang, J., McLeod, L.L., Peterson, H. 1995. Characterization of endothelial cell injury by cholesterol oxidation products found in oxidized LDL. J. Lipid Res. 36, 1971-1986. 

Oxidative stress is now widely believed to be the major mechanism of athero-genesis. Interestingly, it was demonstrated 47 years ago that atheromatous plaques contain abundant lipoperoxides and other lipid peroxidation products (G9). More recently, our understanding of this process was advanced when evidence was provided for significant free radical activity and the lipid oxidative modification hypothesis was presented (P10). A subsequent study provided further evidence that oxidatively modified low-density lipoproteins (LDL) play a major role in the formation of the fatty streak, the earliest visible atherosclerotic lesion, and the subsequent production of the atheroscelrotic plaque (S27). The proposed sequence, which involves arterial endothelial and smooth muscle cells, as well as mono-cytes/macrophages, is as follows (Ql, S25). 

As the knowledge of the pathogenesis of atherosclerosis rapidly increases, it appears that an active vascular endothelium, smooth muscle cells, and blood-borne cells such as monocytes and macrophages all play active roles in the atherosclerotic disease process. Risk factors, such as elevated plasma levels of certain lipids, prooxidants, and cytokines, may contribute to the chronic activation/stimulation as well as to the damage of the endothelium and other vascular tissues (160). There is evidence that supports the hypothesis that it is not only pure cholesterol and saturated fats but rather oxidation products of cholesterol and unsaturated fats (and possibly certain pure unsaturated fats) that are atherogenic, possibly by causing endothelial cell injury/dysfiinction. Lipid-mediated endothelial cell dysfunction may lead to adhesion of monocytes, increased permeability of the endothelium to macromolecules, i.e., a decrease in endothelial barrier function, and disturbances in growth control of the vessel wall. 

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