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J. Biol. Chem. 280 (11): 10040-10046

© 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Resistance to Endotoxic Shock in Endothelial Nitric-oxide Synthase (eNOS) Knock-out Mice

A PRO-INFLAMMATORY ROLE FOR eNOS-DERIVED NO IN VIVO*{diamondsuit}

Linda Connelly{ddagger}, Melanie Madhani, , and Adrian J. Hobbs§

Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6AE, United Kingdom

Abstract: The expression of inducible nitric-oxide synthase (iNOS) and subsequent "high-output" nitric oxide (NO) production underlies the systemic hypotension, inadequate tissue perfusion, and organ failure associated with septic shock. Therefore, modulators of iNOS expression and activity, both endogenous and exogenous, are important in determining the magnitude and time course of this condition. We have shown previously that NO from the constitutive endothelial NOS (eNOS) is necessary to obtain maximal iNOS expression and activity following exposure of murine macrophages to lipopolysaccharide (LPS). Thus, eNOS represents an important regulator of iNOS expression in vitro. Herein, we validate this hypothesis in vivo using a murine model of sepsis. A temporal reduction in iNOS expression and activity was observed in LPS-treated eNOS knock-out (KO) mice as compared with wild-type animals; this was reflected in a more stable hemodynamic profile in eNOS KO mice during endotoxaemia. Furthermore, in human umbilical vein endothelial cells, LPS leads to the activation of eNOS through phosphoinositide 3-kinase- and Akt/protein kinase B-dependent enzyme phosphorylation. These data indicate that the pathogenesis of sepsis is characterized by an initial eNOS activation, with the resultant NO acting as a co-stimulus for the expression of iNOS, and therefore highlight a novel pro-inflammatory role for eNOS.

Received for publication October 22, 2004. Revision received December 17, 2004.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{diamondsuit} This article was selected as a Paper of the Week.

{ddagger} Recipient of a Wellcome Trust International Prize Travelling Research Fellowship.

§ Recipient of a Wellcome Trust Senior Fellowship in Basic Biomedical Sciences. To whom correspondence should be addressed. Tel.: 44-20-7679-6611; Fax: 44-20-7691-3104; E-mail: a.hobbs{at}ucl.ac.uk.

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