Key result
nmMLCK inhibition partially prevents intermittent hypoxia-induced IL-6 secretion and endothelial dysfunction.
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Demonstrates that non-muscular myosin light chain kinase mediates intermittent hypoxia-induced inflammation and vascular impairment, highlighting a potential therapeutic target for sleep apnea.
Obstructive sleep apnea is characterized by intermittent hypoxia (IH) which alters endothelial function, induces inflammation and accelerates atherosclerosis-induced cardiovascular diseases. The non-muscular myosin light chain kinase (nmMLCK) isoform contributes to endothelial cell-cell junction opening. Deletion of nmMLCK protects mice from death in septic shock models and prevents atherosclerosis in high-fat diet-fed mice. The aim of the study was to analyze the implication of nmMLCK in IH-induced vascular inflammation. Human aortic endothelial cells were exposed to 6 hours of IH in absence or presence of nmMLCK inhibitors, ML-7 (5 µM) or PIK (150 µM). IH increased reactive oxygen species (ROS) and nitric oxide (NO) production, p65-NFκB activation and IL-6 secretion. While nmMLCK inhibition did not prevent IH-induced ROS production and p65-NFκB activation, it decreased NO production and partially prevented IL-6 secretion. IH-induced IL-6 secretion and vesicle-associated membrane protein-associated vesicles re-organization were inhibited in presence of the inhibitor of protein secretion, brefeldin A, or ML-7. IH increased monocytes transendothelial migration that was partially prevented by ML-7. Finally, IH reduced endothelium-dependent relaxation to acetylcholine of aortas from wild-type but not those taken from nmMLCK-deficient mice. These results suggest that nmMLCK participates to IH-induced endothelial dysfunction resulting from cytokines secretion and endothelial permeability.
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Recoquillon et al. (2017) studied Intermittent hypoxia-induced vascular inflammation and endothelial dysfunction. nmMLCK inhibitors (ML-7 or PIK) and nmMLCK genetic deletion vs. Absence of nmMLCK inhibitors / wild-type mice exposed to intermittent hypoxia was evaluated on Intermittent hypoxia-induced IL-6 secretion, NO production, monocyte transendothelial migration, and endothelium-dependent relaxation. Inhibition of nmMLCK with ML-7 (5 µM) or PIK (150 µM) decreased NO production and partially prevented IL-6 secretion and endothelial dysfunction during 6 hours of intermittent hypoxia.
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