Inhibition of superoxide generation from neuronal nitric oxide synthase by heat shock protein 90: Implications in NOS regulation

Yao Song, A. J. Cardounel, Jay L. Zweier, Yong Xia

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Besides NO, neuronal NO synthase (nNOS) also produces superoxide (O2-•) at low levels of L-arginine. Recently, heat shock protein 90 (hsp90) was shown to facilitate NO synthesis from eNOS and nNOS. However, the effect of hsp90 on the O2-• generation from NOS has not been determined yet. The interrelationship between its effects on O2-• and NO generation from NOS is also unclear. Therefore, we performed electron paramagnetic resonance measurements of O2-• generation from nNOS to study the effect of hsp90. Purified rat nNOS generated strong O2-• signals in the absence of L-arginine. In contrast to its effect on NO synthesis, hsp90 dose-dependently inhibited O2-• generation from nNOS with an IC50 of 658 nM. This inhibition was not due to O2-• scavenging because hsp90 did not affect the O2-• generated by xanthine oxidase. At lower levels of L-arginine where marked O2-• generation occurred, hsp90 caused a more dramatic enhancement of NO synthesis from nNOS as compared to that under normal L-arginine. Significant O2-• production was detected from nNOS even at intracellular levels of L-arginine. Adding hsp90 prevented this O2-• production, leading to enhanced nNOS activity. Thus, these results demonstrated that hsp90 directly inhibited O2-• generation from nNOS. Inhibition of O2-• generation may be an important mechanism by which hsp90 enhances NO synthesis from NOS.

Original languageEnglish (US)
Pages (from-to)10616-10622
Number of pages7
JournalBiochemistry®
Volume41
Issue number34
DOIs
StatePublished - Aug 27 2002

ASJC Scopus subject areas

  • Biochemistry

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