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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/H1621    most recent 01008.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Calvert, T. J. Articles by Nelin, L. D. Search for Related Content PubMed PubMed Citation Articles by Calvert, T. J. Articles by Nelin, L. D.

Deficiency of mitogen-activated protein kinase phosphatase-1 results in iNOS-mediated hypotension in response to low-dose endotoxin

Centers for Perinatal Research and Gene Therapy, The Research Institute at Nationwide Children's Hospital, and the Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio

Submitted 30 August 2007 ; accepted in final form 11 February 2008

Mitogen-activated protein kinase phosphatase-1 (MKP-1) is essential in limiting the proinflammatory response to lipopolysaccharide (LPS). We hypothesized that Mkp-1^–/– mice would respond to low-dose LPS with a fall in blood pressure due to augmented expression of inducible nitric oxide (NO) synthase (iNOS). To test this hypothesis, Mkp-1^–/– mice and their wild-type littermates were treated with 10 µg/kg iv LPS, and mean arterial blood pressure (MAP) and exhaled NO production (exNO) were measured. Tissues were harvested for an assessment of iNOS protein levels. Wild-type mice had no change in MAP or exNO during the experimental period, whereas Mkp-1^–/– mice had a fall (P < 0.005) in MAP [79 ± 5% of baseline (BL)] and an increase (P < 0.01) in exNO (266 ± 50% of BL) after 150 min. The tissue levels of iNOS were greater in Mkp-1^–/– than in wild-type mice. In additional experiments, 60 min after LPS treatment, Mkp-1^–/– and wild-type mice were given N-nitro-L-arginine methyl ester (L-NAME) or aminoguanidine, and MAP and exNO were monitored for 90 min. Treatment with L-NAME prevented the LPS-induced increase in exNO and decrease in MAP but resulted in decreased exNO and elevated MAP in wild-type mice. Aminoguanidine prevented the increase in exNO and the fall in MAP caused by LPS in Mkp-1^–/– mice, without significantly affecting MAP or exNO in wild-type mice. These results demonstrate that a deficiency of MKP-1 results in an exaggerated hypotensive response to LPS mediated by augmented iNOS expression. We speculate that defects in the Mkp-1 gene may increase susceptibility for the development of septic shock.

lipopolysaccharide; septic shock; cell signaling; nitric oxide