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autoregulatory role of endothelium-derived nitric oxide (NO) on Lipopolysaccharide-induced vascular inducible NO synthase expression and function.
J Biol Chem 2005; 280(8):7236-43JB

Abstract

Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) is responsible for sepsis-induced hypotension and plays a major contributory role in the ensuing multiorgan failure. The present study aimed to elucidate the role of endothelial NO in lipopolysaccharide (LPS)-induced iNOS expression, in isolated rat aortic rings. Exposure to LPS (1 mug/ml, 5 h) resulted in a reversal of phenylephrine precontracted tone in aortic rings (70.7 +/- 3.2%). This relaxation was associated with iNOS expression and NF-kappaB activation. Positive immunoreactivity for iNOS protein was localized in medial and adventitial layers of LPS-treated aortic rings. Removal of the endothelium rendered aortic rings resistant to LPS-induced relaxation (8.9 +/- 4.5%). Western blotting of these rings demonstrated an absence of iNOS expression. However, treatment of endothelium-denuded rings with the NO donor, diethylamine-NONOate (0.1 mum), restored LPS-induced relaxation (61.6 +/- 6.6%) and iNOS expression to levels comparable with arteries with intact endothelium. Blockade of endothelial NOS (eNOS) activation using geldanamycin and radicicol, inhibitors of heat shock protein 90, in endothelium-intact arteries suppressed both LPS-induced relaxation and LPS-induced iNOS expression (9.0 +/- 8.0% and 2.0 +/- 6.2%, respectively). Moreover, LPS treatment (12.5 mg/kg, intravenous, 15 h) of wild-type mice resulted in profound elevation of plasma [NO(x)] measurements that were reduced by approximately 50% in eNOS knock-out animals. Furthermore, LPS-induced changes in vascular reactivity and iNOS expression evident in wild-type tissues were profoundly suppressed in tissues taken from eNOS knockout animals. Together, these data suggest that eNOS-derived NO, in part via activation of NF-kappaB, regulates iNOS-induction by LPS. This study provides the first demonstration of a proinflammatory role of vascular eNOS in sepsis.

Authors+Show Affiliations

Clinical Pharmacology, William Harvey Research Institute, Barts and The London, Charterhouse Square, London, EC1M 6BQ, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15583003

Citation

Vo, Phuong A., et al. "Autoregulatory Role of Endothelium-derived Nitric Oxide (NO) On Lipopolysaccharide-induced Vascular Inducible NO Synthase Expression and Function." The Journal of Biological Chemistry, vol. 280, no. 8, 2005, pp. 7236-43.
Vo PA, Lad B, Tomlinson JA, et al. Autoregulatory role of endothelium-derived nitric oxide (NO) on Lipopolysaccharide-induced vascular inducible NO synthase expression and function. J Biol Chem. 2005;280(8):7236-43.
Vo, P. A., Lad, B., Tomlinson, J. A., Francis, S., & Ahluwalia, A. (2005). Autoregulatory role of endothelium-derived nitric oxide (NO) on Lipopolysaccharide-induced vascular inducible NO synthase expression and function. The Journal of Biological Chemistry, 280(8), pp. 7236-43.
Vo PA, et al. Autoregulatory Role of Endothelium-derived Nitric Oxide (NO) On Lipopolysaccharide-induced Vascular Inducible NO Synthase Expression and Function. J Biol Chem. 2005 Feb 25;280(8):7236-43. PubMed PMID: 15583003.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - autoregulatory role of endothelium-derived nitric oxide (NO) on Lipopolysaccharide-induced vascular inducible NO synthase expression and function. AU - Vo,Phuong A, AU - Lad,Bhavini, AU - Tomlinson,James A P, AU - Francis,Stephanie, AU - Ahluwalia,Amrita, Y1 - 2004/12/06/ PY - 2004/12/8/pubmed PY - 2005/4/9/medline PY - 2004/12/8/entrez SP - 7236 EP - 43 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 280 IS - 8 N2 - Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) is responsible for sepsis-induced hypotension and plays a major contributory role in the ensuing multiorgan failure. The present study aimed to elucidate the role of endothelial NO in lipopolysaccharide (LPS)-induced iNOS expression, in isolated rat aortic rings. Exposure to LPS (1 mug/ml, 5 h) resulted in a reversal of phenylephrine precontracted tone in aortic rings (70.7 +/- 3.2%). This relaxation was associated with iNOS expression and NF-kappaB activation. Positive immunoreactivity for iNOS protein was localized in medial and adventitial layers of LPS-treated aortic rings. Removal of the endothelium rendered aortic rings resistant to LPS-induced relaxation (8.9 +/- 4.5%). Western blotting of these rings demonstrated an absence of iNOS expression. However, treatment of endothelium-denuded rings with the NO donor, diethylamine-NONOate (0.1 mum), restored LPS-induced relaxation (61.6 +/- 6.6%) and iNOS expression to levels comparable with arteries with intact endothelium. Blockade of endothelial NOS (eNOS) activation using geldanamycin and radicicol, inhibitors of heat shock protein 90, in endothelium-intact arteries suppressed both LPS-induced relaxation and LPS-induced iNOS expression (9.0 +/- 8.0% and 2.0 +/- 6.2%, respectively). Moreover, LPS treatment (12.5 mg/kg, intravenous, 15 h) of wild-type mice resulted in profound elevation of plasma [NO(x)] measurements that were reduced by approximately 50% in eNOS knock-out animals. Furthermore, LPS-induced changes in vascular reactivity and iNOS expression evident in wild-type tissues were profoundly suppressed in tissues taken from eNOS knockout animals. Together, these data suggest that eNOS-derived NO, in part via activation of NF-kappaB, regulates iNOS-induction by LPS. This study provides the first demonstration of a proinflammatory role of vascular eNOS in sepsis. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/15583003/autoregulatory_role_of_endothelium_derived_nitric_oxide__NO__on_Lipopolysaccharide_induced_vascular_inducible_NO_synthase_expression_and_function_ DB - PRIME DP - Unbound Medicine ER -