Interaction in endothelium of nmMLCK and the NF-κB pathway is critical to lipopolysaccharide-induced vascular hyporeactivity.

Interaction in endothelium of non-muscular myosin light-chain kinase and the NF-κB pathway is critical to lipopolysaccharide-induced vascular hyporeactivity.

0319 : Non muscular myosin light chain kinase (nmMLCK) and NF-κB pathway interaction in endothelium is critical for lipopolysaccharide-induced vascular hyporeactivity

Volume 7, Issue 2, April 2015, Pages 136 Printemps de la Cardiologie : Recherche Fondamentale et Clinique - Centre de Congrès Pierre Baudis, Toulouse, 2-3 avril 2015 1Faculté de Médecine, INSERM 1063, Angers, France 2Universita de Napoli, Napoli, Italie Available online 6 May 2015 The lipopolysaccharide (LPS) is a major component of the Gram-negative bacteria affects cells of the vasculature causing hypotension by the initiation of smooth muscle cell hyporeactivity and endothelial dysfunction.

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Clin Sci (Lond). 2015 Oct 1;129(8):687-98. doi: 10.1042/CS20140625. Epub 2015 Jun 15.

Recoquillon S1, Carusio N2, Lagrue-Lakhal AH1, Tual-Chalot S1, Filippelli A3, Andriantsitohaina R4, Martinez MC5.

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Abstract

During sepsis, endothelial barrier dysfunction contributes to cardiovascular failure, mainly through the release of oxidative metabolites by penetrant leukocytes. We reported the non-muscular isoform of myosin light chain kinase (nmMLCK) playing a pivotal role in endotoxin shock injury associated with oxidative and nitrative stresses, and vascular hyporeactivity. The present study was aimed at understanding the molecular mechanism of lipopolysaccharide (LPS)-induced vascular alterations as well as studying a probable functional association of nmMLCK with nuclear factor κ-light-chain enhancer of activated B cells (NF-κB). Aortic rings from mice were exposed in vitro to LPS and, then, vascular reactivity was measured. Human aortic endothelial cells (HAoECs) were incubated with LPS, and interaction of nmMLCK with NF-κB was analysed. We provide evidence that nmMLCK deletion prevents vascular hyporeactivity induced by in vitro LPS treatment but not endothelial dysfunction in the aorta. Deletion of nmMLCK inhibits LPS-induced NF-κB activation and increases nitric oxide (NO) release via induction of inducible NO synthase (iNOS) within the vascular wall. Also, removal of endothelium prevented both NF-κB and iNOS expression in aortic rings. Among the proinflammatory factors released by LPS-treated endothelial cells, interleukin-6 accounts for the induction of iNOS on smooth muscle cells in response to LPS. Of particular interest is the demonstration that, in HAoECs, LPS-induced NF-κB activation occurs via increased MLCK activity sensitive to the MLCK inhibitor, ML-7, and physical interactions between nmMLCK and NF-κB. We report for the first time on NF-κB as a novel partner of nmMLCK within endothelial cells. The present study demonstrates a pivotal role of nmMLCK in vascular inflammatory pathologies. 

© 2015 Authors; published by Portland Press Limited.

KEYWORDS: 

NF-κB; inflammation; lipopolysaccharide; nitric oxide; nmMLCK