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1 Research Group Immunobiology, MED-Heinrich-Heine-University of Duesseldorf, Duesseldorf, NRW, Germany
* To whom correspondence should be addressed. E-mail: hemmrich{at}gmx.de.
In endothelial cells the expression of the inducible nitric oxide synthase (iNOS) and the resulting high output nitric oxide (NO) synthesis has 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 (AS)-mediated iNOS knock-down during proinflammatory cytokine challenge in primary endothelial cell cultures and studied endothelial function by monitoring the expression of stress defense genes. Using AS oligonucleotides (ODN) we achieved a block of iNOS protein formation, accompanied by a strong decrease in the expression of the protective stress response genes bcl-2, VEGF, and 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 NO 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, appear to significantly contribute to endothelial dysfunction and death during oxidative stress.
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