Despite minimal hemodynamic alterations endotoxemia modulates NOS and p38-MAPK phosphorylation via metalloendopeptidases.

Abstract

In the present study, we hypothesized that endotoxemia produces metalloendopeptidase (MEPD)-dependent generation of endothelin-1 (ET-1) and alters NOS expression correlating with p38-mitogen-activated protein kinase (MAPK) phosphorylation in thoracic aorta. Male Sprague-Dawley rats (350-400 g) were subjected to two groups randomly; sham-treated (N = 10) and lipopolysaccharide (LPS)-treated (N = 10) (E. coli LPS 2 mg/kg bolus + 2 mg/kg infusion for 30 min). The animals in each group were further subdivided into vehicle and MEPD inhibitor phosphoramidon (1 mg/kg bolus, PHOS)-treated groups. LPS produces a significant decrease in mean arterial pressure (MAP) at 2 h post endotoxemia that was blocked by PHOS. PHOS attenuated LPS-induced increase in tumor necrosis factor-alpha (TNF-alpha) concentration at 2- and 24 h post-LPS administration. LPS significantly elevated plasma concentrations of ET-1 at 2- and 24 h post endotoxemia. An upregulated preproET-1 expression following both LPS and MEPD inhibition was observed in thoracic aorta at 2 h post treatment. PHOS effectively blocked conversion of preproET-1 to ET-1 in thoracic aorta locally at 24 h post treatment in endotoxic rats. PHOS inhibited LPS-induced upregulation of inducible NOS (iNOS), downregulation of endothelial NOS (eNOS) and elevation of NO byproducts (NOx) in thoracic aorta. PHOS also blocked LPS-induced upregulated p38-MAPK phosphorylation in thoracic aorta at 24 h post endotoxemia. The data revealed that LPS induces MEPD-sensitive inflammatory response syndrome (SIRS) at 2- and 24 h post endotoxemia. We concluded that inhibition of MEPD not only decreases the levels of ET-1 but also simultaneously downregulates protein expression of iNOS and phosphorylated p38-MAPK while increasing eNOS in thoracic aorta during SIRS in endotoxemia. We suggest that MEPD-dependent ET-1 and NO mechanisms may be involved in endotoxemia-induced altered p38-MAPK phosphorylation.

• Authors: Akanksha Gupta, Avadhesh C Sharma
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 265 Issue 1-2 Pg. 47-56 (Oct 2004) ISSN: 0300-8177 [Print] Netherlands
• PMID: 15543933 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Endothelin-1
• Glycopeptides
• Lipopolysaccharides
• Nitric Oxide
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nos2 protein, rat
• Nos3 protein, rat
• p38 Mitogen-Activated Protein Kinases
• Metalloendopeptidases
• phosphoramidon

Topics

• Animals
• Aorta, Thoracic (pathology)
• Blood Pressure
• Cytokines (biosynthesis)
• Endothelin-1 (biosynthesis)
• Endotoxemia (enzymology, pathology)
• Glycopeptides (pharmacology)
• Immunoblotting
• Lipopolysaccharides (metabolism)
• Male
• Metalloendopeptidases (chemistry)
• Models, Biological
• Nitric Oxide (chemistry)
• Nitric Oxide Synthase (metabolism)
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• Time Factors
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (metabolism)