Several experimental and clinical studies have shown that oxidized low-density lipoprotein and oxidation-sensitive mechanisms are central in the pathogenesis of vascular dysfunction and atherogenesis. Here, we have used p66 Shc؊/؊ and WT mice to investigate the effects of high-fat diet on both systemic and tissue oxidative stress and the development of early vascular lesions. To date, the p66 Shc؊/؊ mouse is the unique genetic model of increased resistance to oxidative stress and prolonged life span in mammals. Computer-assisted image analysis revealed that chronic 21% highfat treatment increased the aortic cumulative early lesion area by Ϸ21% in WT mice and only by 3% in p66 Shc؊/؊ mice. Early lesions from p66 Shc؊/؊ mice had less content of macrophage-derived foam cells and apoptotic vascular cells, in comparison to the WT. Furthermore, in p66 Shc؊/؊ mice, but not WT mice, we found a significant reduction of systemic and tissue oxidative stress (assessed by isoprostanes, plasma low-density lipoprotein oxidizability, and the formation of arterial oxidation-specific epitopes). These results support the concept that p66 Shc؊/؊ may play a pivotal role in controlling systemic oxidative stress and vascular diseases. Therefore, p66 Shc might represent a molecular target for therapies against vascular diseases.atherosclerosis ͉ oxygen radicals ͉ transgenic mouse T he p66Shc protein is one of the three isoforms encoded by the mammalian Shc locus. The Shc overlapping proteins (p66 Shc , p52 Shc , and p46 Shc ) share a C-terminal Src homology 2 (SH2) domain, a central collagen-homologous (CH) region, and an N-terminal phosphotyrosine binding domain and differ for N termini of different lengths. P66 Shc , in particular, is characterized by an additional CH region at the N terminus. Shc proteins are cytoplasmic substrates of activated tyrosine kinases and have been implicated in the transmission of activation signals from tyrosine kinases to Ras proteins (1-3). In 1999, it became clear that Shc proteins might serve broad cellular functions. Homozygous mutation of p66Shc in mice was shown to induce increased resistance to oxidative stress and lifespan extension (4). Recently, it has been demonstrated that the p66 Shc longevity gene increases intracellular reactive oxygen species (ROS), thereby affecting the rate of oxidative damage to nucleic acids; in advance p66 Shc function on ROS, metabolism is necessary for appropriate p53-dependent apoptosis (5).Cells within the arterial wall produce several species of free radicals, and, as is well known, an important functional index of healthy status is represented by vascular function (reviewed in refs. 6 and 7). A multitude of clinical studies and reports with experimental animal models have shown that oxidized lowdensity lipoprotein (oxLDL) and redox-sensitive pathways are key modulators of vascular dysfunction and atherogenesis (reviewed in refs. 8-10). Interestingly, oxLDL and its byproducts may induce early proatherogenic events not only in adults but also in arteries of the ...

Serotonin has a vasodilating effect on normal human coronary arteries; when the endothelium is damaged, as in coronary artery disease, serotonin has a direct, unopposed vasoconstricting effect. When considered with other evidence, these data suggest that platelet-derived factors such as serotonin may have a role in certain acute coronary ischemic syndromes.

To test whether generation of oxygen radicals during postischemic reperfusion might promote peroxidation of cardiac membrane lipids, four groups of Langendorff-perfused rabbit hearts were processed at the end of (a) control perfusion, (b) 30 min of total global ischemia at 370C without reperfusion, (c) 30 min of ischemia followed by reperfusion with standard perfusate, (d) 30 min of ischemia followed by reperfusion with the oxygen radical scavenger human recombinant superoxide dismutase (h-SOD). The left ventricle was homogenized and tissue content of malonyldialdehyde (MDA), an end product of lipid peroxidation, was measured on the whole homogenate as well as on various subcellular fractions. Reperfusion was accompanied by a significant increase in MDA content of the whole homogenate and of the fraction enriched in mitochondria and lysosomes. This phenomenon was not observed in hearts subjected to ischemia but not reperfused, and was similarly absent in those hearts which received h-SOD at reflow. Reperfused hearts also had significantly greater levels of conjugated dienes (another marker of lipid peroxidation) in the mitochondrial-lysosomal fraction. Again, this phenomenon did not occur in ischemic hearts or in reperfused hearts treated with h-SOD. Unlike the effect on tissue MDA and conjugated dienes, reperfusion did not significantly stimulate release of MDA in the cardiac effluent. Treatment with h-SOD was also associated with significant improvement in the recovery ofcardiac function. In conclusion, these data directly demonstrate that postischemic reperfusion results in enhanced lipid peroxidation of cardiac membranes, which can be blocked by h-SOD, and therefore is most likely secondary to oxygen radical generation at reflow. (J. Clin.

Abstract-Maternal hypercholesterolemia during pregnancy is associated with enhanced fatty streak formation in human fetuses and faster progression of atherosclerosis during childhood even under normocholesterolemic conditions. A causal role of maternal hypercholesterolemia in lesion formation during fetal development has previously been established in rabbits. The same experimental model is now used to establish that maternal hypercholesterolemia or ensuing pathogenic events in fetal arteries enhance atherogenesis later in life. Five groups of rabbit mothers were fed chow, cholesterol-enriched chow, or cholesterol-enriched chow plus 1000 IU vitamin E, 3% cholestyramine, or both during pregnancy. Offspring of all groups (nϭ136) were fed a mildly hypercholesterolemic diet for up to a year and had similar cholesterol levels. Aortic lesion sizes and lipid peroxidation products in plasma and lesions in offspring were determined at birth, 6 months, or 12 months. Lesion progression in offspring of hypercholesterolemic mothers was greater than in all other groups. At each time point, offspring of hypercholesterolemic mothers had 1.5-to 3-fold larger lesions than offspring of normocholesterolemic mothers (PϽ0.01), with the greatest absolute differences at 12 months. Maternal treatment reduced lesions by 19% to 53%, compared with offspring of untreated hypercholesterolemic mothers (PϽ0.01), with the greatest effect in the vitamin E groups. At 12 months, lesions in offspring of all vitamin E and cholestyramine-treated mothers were similar to those of normocholesterolemic mothers. Lipid peroxidation end-products in lesions and plasma showed analogous differences between groups as lesions (PϽ0.01). Thus, pathogenic programming in utero increases the susceptibility to atherogenic risk factors later in life and maternal intervention with cholesterol-lowering drugs or antioxidants reduce postnatal lipid peroxidation and atherosclerosis in their offspring.