Activation of endothelial nitric oxide synthase by the pro-apoptotic drug embelin: Striking discrepancy between nitric oxide-mediated cyclic GMP accumulation and l-citrulline formation

Kurt Schmidt, Jens Martens-Lobenhoffer, Andreas Meinitzer, Wolfgang F. Graier, Christina M. Torres, Richard C Venema, Bernd Mayer

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The benzoquinone derivative embelin is a multifunctional drug that not only induces apoptosis by inhibiting XIAP, the X chromosome-linked inhibitor of apoptosis protein, but also blocks nuclear factor-κB signaling pathways, thereby leading to down-regulation of a variety of gene products involved in tumor cell survival, proliferation, invasion, angiogenesis, and inflammation. Here, we report that embelin activates and modulates l-arginine/nitric oxide/cyclic GMP signaling in cultured endothelial cells. Embelin elicited a rapid increase of intracellular free Ca2+, leading to activation of endothelial nitric oxide synthase (eNOS) and NO-induced cGMP accumulation. While the cGMP response was comparable to that caused by other Ca2+-mobilizing agents, the stimulatory effect of embelin on l-citrulline formation (∼4-fold) was substantially lower than that observed upon activation of eNOS with the Ca2+ ionophore A23187 (∼18-fold), the receptor agonist ATP (∼16-fold) or the sarco-endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin (∼14-fold). The apparent discrepancy between NO/cGMP and l-citrulline formation in embelin-treated cells was not due to enhanced metabolism and/or efflux of l-citrulline, increased NO bioavailability, inhibition of cGMP hydrolysis, sensitization of soluble guanylate cyclase (sGC) to NO, or enhanced formation of a sGC/eNOS complex. Our puzzling observations suggest that embelin improves coupling of endothelial NO synthesis to sGC activation through mobilization of an as yet unrecognized signaling pathway.

Original languageEnglish (US)
Pages (from-to)281-289
Number of pages9
JournalNitric Oxide - Biology and Chemistry
Volume22
Issue number4
DOIs
StatePublished - May 15 2010

Keywords

  • Embelin
  • Endothelial nitric oxide synthase
  • Nitric oxide
  • Soluble guanylate cyclase
  • cGMP
  • l-Citrulline

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Clinical Biochemistry
  • Cancer Research

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