Non-muscular myosin light chain kinase triggers intermittent hypoxia-induced interleukin-6 release, endothelial dysfunction and permeability

Abstract

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.

Ethyl Acetate Fraction of Lannea microcarpa Engl. and K. Krause (Anacardiaceae) Trunk Barks Corrects Angiotensin II-Induced Hypertension and Endothelial Dysfunction in Mice

“…Ex vivo vasorelaxation experiments were conducted on thoracic aorta according to the method previously described [25]. Upon mouse euthanasia, the thoracic aorta was removed and pinned in a dissecting dish and cleaned of fat and connective tissue.…”

PI16 is a non-neuronal regulator of neuropathic pain

“…We found in response to SNI Pi16−/− mice have reduced Mlck expression and correspondingly, repressed phospho-MLC2 activation in DRG and sciatic nerve. MLCK and its substrate MLC2 maintain integrity of endothelial barrier and their function has been highlighted in diseased models of lung injury, pancreatitis, and atherosclerosis 20,28–30 . In a mouse model of lung injury in response to endotoxin lipopolysaccharide, MLCK−/− mice preserve endothelial barrier function compared to wildtype and show reduced leukocyte infiltration in lungs 31 .…”

Emodin, A Chinese Herbal Medicine, Inhibits Reoxygenation-Induced Injury in Cultured Human Aortic Endothelial Cells by Regulating the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) and Endothelial Nitric Oxide Synthase (eNOS) Signaling Pathway

“…TNF-α causes oxidative stress in vascular endothelial cells and activates several pro-inflammatory nuclear factors such as NF-κB, which further induces synthesis of more inflammatory cytokines [ 19 ]. IL-6 is involved in increasing vascular permeability under clinical situations that include myocardial infarction and stroke [ 20 ]. IL-8 plays a role in platelets aggregation and activation contributing to the formation of thrombosis [ 21 ].…”