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
; 22(4): 281-9, 2010 May 15.
Article
em En
| MEDLINE
| ID: mdl-20144727
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Benzoquinonas
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Citrulina
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Apoptose
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GMP Cíclico
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Células Endoteliais
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Óxido Nítrico Sintase Tipo III
Limite:
Animals
Idioma:
En
Revista:
Nitric Oxide
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Áustria