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

Hantamalala Ralay Ranaivo^*, Nunzia Carusio^*, Rosemary Wangensteen^*, Patrick Ohlmann^*, Cecile Loichot^*, Angela Tesse^*, Karel Chalupsky^*, Irina Lobysheva, Jacques Haiech, D. Martin Watterson^* and Ramaroson Andriantsitohaina^*

From Unité Mixte de Recherche (UMR) Centre National de la Recherche Scientifique (CNRS) 7034,^* Faculté de Pharmacie, Illkirch, France; the Center for Drug Discovery and Chemical Biology, Northwestern University, Chicago, Illinois; UMR INSERM 771–CNRS 6214, Faculté de Médecine, Angers, France; and Institute of Chemical Physics RAS, Moscow, Russia

This study investigated the consequences of deletion of thelong isoform of myosin light chain kinase (MLCK210) on the cardiovascularchanges induced by the bacterial endotoxin lipopolysaccharide(LPS) and cecal ligation puncture using MLCK210^–/–mice. Here, we provide evidence that deletion of MLCK210 enhancedsurvival after intraperitoneal injection of LPS or cecal ligationpuncture. LPS-induced vascular hyporeactivity to vasoconstrictoragents was completely prevented in aorta from MLCK210^–/–mice. This was associated with a decreased up-regulation ofnuclear facor- ${kappa}$ B expression and activity, inducible nitric-oxidesynthase, and level of oxidative stress in the vascular media.Furthermore, LPS-induced increase of nitric oxide productionin the circulation and tissues (including heart, liver, andlung) that was correlated with an increased expression of induciblenitric-oxide synthase was also reduced in MLCK210^–/–mice. These data demonstrate a role for MLCK210 in endotoxinshock injury associated with oxidative and nitrosative stressesand vascular hyporeactivity.