Protection Against Endotoxic Shock as a Consequence of Reduced Nitrosative Stress in MLCK210-Null Mice

Abstract

This study investigated the consequences of deletion of the long isoform of myosin light chain kinase (MLCK210) on the cardiovascular changes induced by the bacterial endotoxin lipopolysaccharide (LPS) and cecal ligation puncture using MLCK210 ؊/؊ mice. Here, we provide evidence that deletion of MLCK210 enhanced survival after intraperitoneal injection of LPS or cecal ligation puncture. LPS-induced vascular hyporeactivity to vasoconstrictor agents was completely prevented in aorta from MLCK210 ؊/؊ mice. This was associated with a decreased up-regulation of nuclear facor-B expression and activity, inducible nitric-oxide synthase, and level of oxidative stress in the vascular media. Furthermore, LPS-induced increase of nitric oxide production in the circulation and tissues (including heart, liver, and lung) that was correlated with an increased expression of inducible nitric-oxide synthase was also reduced in MLCK210 ؊/؊ mice. These data demonstrate a role for MLCK210 in endotoxin shock injury associated with oxidative and nitrosative stresses and vascular hyporeactivity.

Nonmuscle Myosin Light Chain Kinase: A Key Player in Intermittent Hypoxia‐Induced Vascular Alterations

“…Thus, as opposed to the response of their wild‐type counterparts, the absence of oxidative stress under IH exposure in nmMLCK −/− mice could contribute to the conservation of vascular properties. Interestingly, this result is in accordance with a previous study describing the same protective effect of nmMLCK deletion on vascular oxidative stress in a model of lipopolysaccharide‐induced sepsis 20. We further demonstrated that nmMLCK inhibition abolishes the IH‐induced endothelial barrier dysfunctions, which could directly result from the prevention of oxidative stress47 and could explain the limitation of inflammation in the vascular wall of nmMLCK −/− compared with nmMLCK +/+ mice.…”

“…In endothelial cells, this retraction is linked to endothelial permeability enhancement and vascular leakage under proinflammatory conditions. In this context, an activation of the nmMLCK has been linked to several pathophysiological conditions, such as vascular inflammation and atherosclerosis,18 acute lung injury,19 endotoxic shock,20 and severe burns 21…”

Antimicrobial peptide Cathelicidin-BF prevents intestinal barrier dysfunction in a mouse model of endotoxemia

“…Activated NF-κB p65 may bind to the myosin light-chain kinase (MLCK) promoter region and increase MLCK expression [33,34]. MLCK-mediated MLC phosphorylation has been found to result in the contraction of actin-myosin filaments, altering TJ protein localization and expression as well as TJ barrier functional openings [35]. The results presented here showed that C-BF markedly inhibited NF-κB activation which may suppress the activation of MLCK and reduce the disruption of TJs.…”

Matrix Metalloproteinases as Drug Targets in Infections Caused by Gram-Negative Bacteria and in Septic Shock

“…or i.p. injection of LPS, which on its own reproduces many of the features of gram-negative sepsis (19,120). This model induces endotoxemia, is very acute, enables precise dosing, and is highly reproducible, but no infection is involved, which makes the model somewhat less relevant to sepsis in humans.…”