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

Abstract

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 Nω-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.