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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.

SUBMITTER: Recoquillon S

PROVIDER: S-EPMC5651916 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Hypoxia-inducible factor-1 mediates pancreatic β-cell dysfunction by intermittent hypoxia.

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Intermittent hypoxia exacerbates pancreatic ?-cell dysfunction in a mouse model of diabetes mellitus.

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Intermittent Hypoxia ageing

Project description:Intermittent Hypoxia ageing

| PRJNA263964 | ENA

Tubular injury triggers podocyte dysfunction by ?-catenin-driven release of MMP-7.

Project description:Proteinuric chronic kidney disease (CKD) remains a major health problem worldwide. While it is well established that the progression of primary glomerular disease induces tubulointerstitial lesions, how tubular injury triggers glomerular damage is poorly understood. We hypothesized that injured tubules secrete mediators that adversely affect glomerular health. To test this, we used conditional knockout mice with tubule-specific ablation of ?-catenin (Ksp-?-cat-/-) and subjected them to chronic angiotensin II (Ang II) infusion or Adriamycin. Compared with control mice, Ksp-?-cat-/- mice were dramatically protected from proteinuria and glomerular damage. MMP-7, a downstream target of ?-catenin, was upregulated in treated control mice, but this induction was blunted in the Ksp-?-cat-/- littermates. Incubation of isolated glomeruli with MMP-7 ex vivo led to nephrin depletion and impaired glomerular permeability. Furthermore, MMP-7 specifically and directly degraded nephrin in cultured glomeruli or cell-free systems, and this effect was dependent on its proteolytic activity. In vivo, expression or infusion of exogenous MMP-7 caused proteinuria, and genetic ablation of MMP-7 protected mice from Ang II-induced proteinuria and glomerular injury. Collectively, these results demonstrate that ?-catenin-driven MMP-7 release from renal tubules promotes glomerular injury via direct degradation of the key slit diaphragm protein nephrin.

| S-EPMC6975262 | biostudies-literature

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