Editors' ChoiceSEPSIS

A Shocking Effect of eNOS

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Science's STKE  22 Mar 2005:
Vol. 2005, Issue 276, pp. tw107
DOI: 10.1126/stke.2762005tw107

Nitric oxide synthase (NOS) exists in constitutively expressed isoforms (neuronal nNOS and endothelial eNOS) and an inducible isoform (iNOS) that is not apparent under basal conditions. Proinflammatory cytokines and lipopolysaccharides (LPS) stimulate the transcription of iNOS and thereby the production of nitric oxide (NO), which is involved in antibacterial defenses. Overproduction of NO, however, has been implicated in the systemic hypotension and organ failure seen in septic shock. Connelly et al., who had previously shown that eNOS facilitated macrophage production of iNOS in response to LPS, used eNOS-knockout mice to investigate the role of eNOS in a mouse model of sepsis. The hypotensive effect of LPS on mean arterial blood pressure was markedly attenuated in the eNOS knockout mice, as was the LPS-mediated increase in the plasma concentration of NO2 and NO3 and in the abundance of iNOS protein. LPS transiently stimulated the phosphorylation of the serine-threonine protein kinase Akt and of eNOS in cultured human umbilical vein endothelial cells (HUVECs). Similarly, LPS transiently stimulated Akt phosphorylation in bone marrow-derived macrophages (BMDM∅s) from both wild-type and knockout mice. Pharmacological analysis in wild-type and knockout BMDM∅s indicated that the phosphoinositide 3-kinase (PI3K)-Akt pathway was involved in LPS-mediated activation of eNOS and the subsequent increases in guanosine 3′,5′-monophosphate (cGMP) accumulation and iNOS expression. Thus, activation of eNOS appears to play an important role in stimulating iNOS transcription in vivo and thereby in the pathogenesis of septic shock.

L. Connelly, M. Madhani, A. J. Hobbs, Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice. J. Biol. Chem. 280, 10040-10046 (2005). [Abstract] [Full Text]

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