EXPRESSION OF EXTRACELLULAR SOD AND INOS IN MACROPHAGES AND SMOOTH-MUSCLE CELLS IN HUMAN AND RABBIT ATHEROSCLEROTIC LESIONS - COLOCALIZATION WITH EPITOPES CHARACTERISTIC OF OXIDIZED LDL AND PEROXYNITRITE-MODIFIED PROTEINS

Oxidative processes play an important role in atherogenesis. Because s uperoxide anion and nitric oxide (NO) are important mediators in vascu lar pathology, we studied the expression of extracellular-superoxide d ismutase (EC-SOD) and inducible nitric oxide synthase (iNOS) in human and rabbit atherosclerotic lesions by using simultaneous in situ hybri dization and immunocytochemistry and EC-SOD enzyme activity measuremen ts, We also analyzed the presence in the arterial wall of oxidized lip oproteins and peroxynitrite-modified proteins as indicators of oxidati ve damage and possible mediators in vascular pathology. EC-SOD and iNO S mRNA and protein were expressed in smooth muscle cells and macrophag es in early and advanced lesions. The expression of both enzymes was e specially prominent in macrophages, As measured by enzyme activity, EC -SOD was the major SOD isoenzyme in the arterial wall. EC-SOD activity was higher in highly cellular rabbit lesions but lower in advanced, c onnective tissue-rich human lesions, Despite the abundant expression o f EC-SOD, malondialdehyde-lysine and hydroxynonenal-lysine epitopes ch aracteristic of oxidized lipoproteins and nitrotyrosine residues chara cteristic of peroxynitrite-modified proteins were detected in iNOS-pos itive, macrophage-rich lesions, thus implying that malondialdehyde, hy droxynonenal, and peroxynitrite are important mediators of oxidative d amage, We conclude that EC-SOD, iNOS, and the balance between NO and s uperoxide anion play important roles in atherogenesis. EC-SOD and iNOS are highly expressed in lesion macrophages. High EC-SOD expression in the arterial wall may be required not only to prevent deleterious eff ects of superoxide anion but also to preserve NO activity and prevent peroxynitrite formation, Modulation of arterial EC-SOD and iNOS activi ties could provide means to protect arteries against atherosclerotic v ascular disease.