PubMed · 6402738
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D Shaw. 1983-02-23. Chelation therapy.. https://pubmed.ncbi.nlm.nih.gov/6402738/
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Atherosclerotic lesions are found opposite vascular flow dividers at sites of low shear stress and oscillatory flow. Since endothelial proinflammatory genes prominent in lesions are regulated by oxidation-sensitive transcriptional control mechanisms, we examined the redox state of cultured human umbilical vein endothelial cells after either oscillatory or steady laminar fluid shear stress. Endothelial oxidative stress was assessed by measuring activity of the superoxide (O2.- )-producing NADH oxidase (a major source of reactive oxygen species in vascular cells), intracellular O2.- levels, induction of the redox-sensitive gene heme oxygenase-1 (HO-1), and abundance of Cu/Zn superoxide dismutase (Cu/Zn SOD), an antioxidant defense enzyme whose level of expression adapts to changes in oxidative stress. When cells were exposed to oscillatory shear (+/-5 dyne/cm2, 1 Hz) for 1, 5, and 24 hours, NADH oxidase activity and the amount of HO-1 progressively increased up to 174+/-16% (P<0.05) and 505+/-111% (P<0.05) versus static conditions, respectively, whereas levels of Cu/Zn SOD remained unchanged. This upregulation of HO-1 was completely blocked by the antioxidant N-acetylcysteine (NAC, 20 mmol/L). In contrast, steady laminar shear (5 dyne/cm2) induced NADH oxidase activity and NAC-sensitive HO-1 mRNA expression only at 1 and 5 hours, a transient response that returned toward baseline at 24 hours. Levels of Cu/Zn SOD mRNA and protein were increased after 24 hours of steady laminar shear. Furthermore, intracellular O2.-, as measured by dihydroethidium fluorescence, was higher in cells exposed to oscillatory than to laminar shear. These data are consistent with the hypothesis that continuous oscillatory shear causes a sustained activation of pro-oxidant processes resulting in redox-sensitive gene expression in human endothelial cells. Steady laminar shear stress initially activates these processes but appears to induce compensatory antioxidant defenses. We speculate that differences in endothelial redox state, orchestrated by different regimens of shear stress, may contribute to the focal nature of atherosclerosis.
The importance of vascular inflammation in the atherosclerotic process is receiving increasing attention. Several infections have been linked with cardiovascular disease and atherogenesis, and the risk of cardiovascular manifestations has been found to be increased in the presence of autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. Inflammatory cytokines have been shown to induce changes in lipid metabolism and endothelial function, which may result in arterial disease. These recent advances in our knowledge may provide a basis for the development of new strategies for the prevention and treatment of atherosclerosis and cardiovascular disease.
Lipid-lowering therapy reduces cardiovascular morbidity and mortality. Although atherosclerotic plaques regress under lipid-lowering therapy, only minor changes in arteriosclerotic plaques are angiographically detectable. These changes cannot fully explain all the benefits of lipid-lowering therapy. Additional factors independent of macroscopically detectable alterations in plaque size may contribute to the clinical effects of lipid-lowering therapy. Qualitative changes in the composition of atherosclerotic plaques may reduce the risk of subsequent plaque rupture. Furthermore, hypercholesterolemia is associated with endothelial dysfunction, i.e., impaired endothelium-mediated vasodilation, induction of adhesion molecules, and altered expression of growth factors. Lipid lowering seems to reverse endothelial dysfunction. Also, lipid-lowering therapy may reduce peripheral arterial resistance and hyperinsulinemia, and may improve erythrocyte deformability. These effects of lipid-lowering therapy may contribute to the clinical benefits. In particular, the concept of endothelial dysfunction as a first, reversible manifestation of target organ damage deserves further attention in the diagnosis and therapy of cardiovascular disease.