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iNOS activity is essential for endothelial stress gene expression protecting against oxidative damage

Research Group Immunobiology, Heinrich-Heine-University of Düsseldorf, D-40001 Düsseldorf, Germany

Submitted 26 April 2003 ; accepted in final form 24 July 2003

In endothelial cells, the expression of the inducible nitric oxide synthase (iNOS) and the resulting high-output nitric oxide synthesis have often been assumed as detrimental to endothelial function, but recent publications have demonstrated a protective role resulting from iNOS espression and activity. To address this question, we used antisense-mediated iNOS knockdown during proinflammatory cytokine challenge in primary endothelial cell cultures and studied endothelial function by monitoring the expression of stress defense genes. Using antisense oligonucleotides, we achieved a block of iNOS protein formation, accompanied by a strong decrease in the expression of the protective stress response genes bcl-2, vascular endothelial growth factor, and heme oxygenase-1 (HO-1). Additionally, cells were also maintained in the presence of limited exogenous substrate concentrations during cytokine challenge, thereby mimicking a situation of low serum arginine level during inflammation. Under these conditions, cytokine addition results in full iNOS protein expression with minimal nitric oxide formation, concomitant with a significant reduction in stress response gene expression and susceptibility to cell death induced by reactive oxygen species. Taken together, our data suggest that cytokine-induced endogenous iNOS expression and activity have key functions in increasing endothelial survival and maintaining function. Thus suppression of iNOS expression or limited substrate supply, as has been reported to occur in atherosclerosis patients, appears to significantly contribute to endothelial dysfunction and death during oxidative stress.

vascular endothelium; inflammation; atherosclerosis; oxidative stress; antisense oligonucleotides; inducible nitric oxide synthase

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