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

Recoquillon, Sylvain; Carusio, Nunzia; Lagrue-Lak-Hal, Anne-Hélène; Tual‐Chalot, Simon; Filippelli, Amelia; Andriantsitohaina, Ramaroson; Martinez, Maria Carmen

doi:10.1042/cs20140625

Cited by 10 publications

(15 citation statements)

References 26 publications

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“…In this respect, nmMLCK has been reported to contain amino acid sequence motifs associated with subcellular targeting or protein-protein interactions in the proteome ( Lin et al, 1999 ; Smith et al, 2002 ). This domain of the enzyme plays a role as a cellular organizer, providing integration among diverse protein including cytoskeletal proteins ( Kudryashov et al, 2004 ) and NF-κB ( Recoquillon et al, 2015 ). Congruent with that hypothesis, MLCK activity has been shown to drive TNFα-dependent NF-κB activation and amplification.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study shows that nmMLCK is involved in lethal complications as well as in the vascular reactivity changes associated with endotoxic shock ( Ralay Ranaivo et al, 2007 ). nmMLCK is linked to LPS-induced up-regulation of NF-κB and increased oxidative and nitrative stresses ( Recoquillon et al, 2015 ). The present study and our former reports underscore that inoculation of MVs from nmMLCK-deficient mice into wild type mice or the use of nmMLCK-deficient mice display similar protective effect in the experimental model of endotoxic shock used in terms of oxidative/nitrative stress, vascular and tissular dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…MVs nmMLCK+/+ or MVs nmMLCK-/- have been taken from mice that have not been treated with LPS. Cells were treated for 24 h with MVs at circulating levels detected in the plasma of mice, in the absence or presence of LPS (Sigma-Aldrich, St Quentin Fallavier, France; 10 μg/ml; Recoquillon et al, 2015 ).…”

Section: Methodsmentioning

confidence: 99%

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Activation of Endothelial Pro-resolving Anti-Inflammatory Pathways by Circulating Microvesicles from Non-muscular Myosin Light Chain Kinase-Deficient Mice

Gaceb¹,

Vergori²,

Martinez³

et al. 2016

Front. Pharmacol.

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Microvesicles, small membrane vesicles released from cells, have beneficial and/or deleterious effects in sepsis. We previously reported that non-muscle myosin light chain kinase (nmMLCK) deletion protects mice against endotoxic shock by reducing inflammation. Here, we have evaluated the consequences of nmMLCK deletion on microvesicle phenotypes and their effects on mouse aortic endothelial cells in association with vascular inflammation and endothelial dysfunction during endotoxic shock induced by lipopolysaccharide in mice. Treatment with lipopolysaccharide induced an increase in levels of circulating microvesicles in wild type but not in nmMLCK-deficient mice. Microvesicles from nmMLCK-deficient mice (MVsnmMLCK-/-) prevented the inflammatory effects of lipopolysaccharide with concomitant increase of anti- inflammatory and reduction of pro-inflammatory secretome in mouse aortic endothelial cells. In addition, MVsnmMLCK-/- reduced the efficacy of lipopolysaccharide to increase aortic oxidative and nitrosative stresses as well as macrophage infiltration in the aorta. Moreover, MVsnmMLCK-/- prevented ex vivo endothelial dysfunction, vascular hyporeactivity, and in vivo overproduction of nitric oxide in heart and liver in response to lipopolysaccharide. Altogether, these findings provide evidence that nmMLCK deletion generates circulating microvesicles displaying protective effects by activating endothelial pro-resolving anti-inflammatory pathways allowing the effective down-regulation of oxidative and nitrative stresses associated with endotoxic shock. Thus, nmMLCK plays a pivotal role in susceptibility to sepsis via the control of cellular activation and release of circulating microvesicles.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Activation of Endothelial Pro-resolving Anti-Inflammatory Pathways by Circulating Microvesicles from Non-muscular Myosin Light Chain Kinase-Deficient Mice

Gaceb¹,

Vergori²,

Martinez³

et al. 2016

Front. Pharmacol.

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“…Although IL-6 can activate both proinflammatory and anti-inflammatory pathways, IL-6 levels correlate with mortality risk from sepsis and ARDS 11. Interestingly, while IL-6 increases iNOS activity in aortic smooth muscle cells16 and it is associated with a drop in systemic blood pressure in patients with septic shock,17 the levels of IL-6 correlate with PAP in patients with PH secondary to COPD or cirrhosis18 19 and have a negative impact on survival in patients with pulmonary arterial hypertension (PAH) 20. Indeed, a therapeutic potential for IL-6 blockade has been demonstrated by neutralising antibodies in experimental models of chronic PH 21.…”

Section: Introductionmentioning

confidence: 93%

Role of acid sphingomyelinase and IL-6 as mediators of endotoxin-induced pulmonary vascular dysfunction

Pandolfi

Barreira

Moreno

et al. 2016

Thorax

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“…Previous studies demonstrated that LPS-induced vascular hyporeactivity was associated with the suppression of small guanosine triphosphate-binding proteins, including RhoA, ROCK and non-muscular isoform of myosin light chain kinase activities (15,39,40). However, the RhoA/ROCK pathway is involved in the hemorrhagic shock-induced vascular hyporeactivity (41–44).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol enhances vascular reactivity in mice following lipopolysaccharide challenge via the RhoA-ROCK-MLCP pathway

Wang

Zhang

et al. 2017

Experimental and Therapeutic Medicine

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The aim of the present study was to identify whether sepsis-induced vascular hyporeactivity is associated with microcirculation disturbance and multiple organ injuries. The current study assessed the impact of resveratrol (Res) treatment on lipopolysaccharide (LPS) challenge mediated vascular hyporeactivity. Effects of Res treatment (30 mg/kg; i.m.) at 1 h following LPS stimulation (5 mg/kg; i.v.) on the survival time, mean arterial pressure (MAP), and maximal difference of MAP (ΔMAP) to norepinephrine (NE; 4.2 µg/kg) in mice were observed. The reactivity to gradient NE of isolated mesenteric arterioles and the association with the RhoA-RhoA kinase (ROCK)-myosin light chain phosphatase (MLCP) pathway were investigated by myography, and the signaling molecule protein levels were assessed using ELISA. Res treatment prolonged the survival time of mice subjected to LPS challenge, but did not prevent the LPS-induced hypotension and increase in ΔMAP. Res treatment and RhoA agonist U-46619 incubation prevented LPS-induced vascular hyporeactivity ex vivo, which were suppressed by incubation with ROCK inhibitor Y-27632. LPS-induced vascular hyporeactivity was not affected by the MLCP inhibitor okadaic acid incubation, but was further downregulated by the co-incubation of OA plus Y-27632. The inhibiting effect of Y-27632 on Res treatment was eradicated by incubation with U-46619. Furthermore, RhoA inhibitor C3 transferase did not significantly inhibit the enhancing role of Res treatment, which was further increased by U-46619 plus C3 transferase co-incubation. In addition, Res treatment eradicated the LPS-induced decreases in p-RhoA and p-Mypt1 levels and increases in MLCP levels. The results of the present study indicate that post-treatment of Res significantly ameliorates LPS-induced vascular hyporeactivity, which is associated with the activation of the RhoA-ROCK-MLCP pathway.

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

Cited by 10 publications

References 26 publications

Activation of Endothelial Pro-resolving Anti-Inflammatory Pathways by Circulating Microvesicles from Non-muscular Myosin Light Chain Kinase-Deficient Mice

Activation of Endothelial Pro-resolving Anti-Inflammatory Pathways by Circulating Microvesicles from Non-muscular Myosin Light Chain Kinase-Deficient Mice

Role of acid sphingomyelinase and IL-6 as mediators of endotoxin-induced pulmonary vascular dysfunction

Resveratrol enhances vascular reactivity in mice following lipopolysaccharide challenge via the RhoA-ROCK-MLCP pathway

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