Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Schmidt, K; Martens-Lobenhoffer, J; Meinitzer, A; Graier, WF; Torres, CM; Venema, RC; Mayer, B.
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.
Nitric Oxide. 2010; 22(4): 281-289.
Doi: 10.1016/j.niox.2010.02.001
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- Co-Autor*innen der Med Uni Graz
- Graier Wolfgang
- Meinitzer Andreas
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- 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-kappaB 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 Ca(2+), 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 Ca(2+)-mobilizing agents, the stimulatory effect of embelin on l-citrulline formation (approximately 4-fold) was substantially lower than that observed upon activation of eNOS with the Ca(2+) ionophore A23187 (approximately 18-fold), the receptor agonist ATP (approximately 16-fold) or the sarco-endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin (approximately 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Apoptosis -
- Benzoquinones - pharmacology
- Citrulline - biosynthesis
- Cyclic GMP - metabolism
- Endothelial Cells - enzymology
- Nitric Oxide - metabolism
- Nitric Oxide Synthase Type III - metabolism
- Signal Transduction -
- Find related publications in this database (Keywords)
- Embelin
- Endothelial nitric oxide synthase
- L-Citrulline
- Nitric oxide
- Soluble guanylate cyclase
- cGMP