Role of nonmuscular myosin light chain kinase in the systemic inflammation, vascular remodeling and vascular outcomes during obstructive sleep apnea – nmMLCK-OSA

Scientific rationale and hypothesis: Obstructive sleep apnea (OSA) is a worldwide public health problem, affecting at least 5% of the general population and characterized by repetitive upper airway occlusions during sleep leading to intermittent hypoxia (IH). Patients with OSA exhibit increased cardiovascular morbidity and mortality, including systemic hypertension, coronary heart disease, arrhythmias and stroke. Treatment of patients with continuous positive airway pressure (CPAP) improves quality of life and daytime sleepiness. However, the major barriers to CPAP treatment are adherence and its failure to alter metabolic or inflammatory markers in obese OSA. Thus a combination of multiple modalities of treatment is needed. The nonmuscle myosin light chain kinase (nmMLCK) isoform is a protein that contributes to endothelial cell-cell junction opening, monocyte migration and therefore participates in inflammation. We have described cardiovascular dysfunction, mainly endothelial dysfunction, associated with inflammation and oxidative stress in OSA patients. Also, circulating levels of microparticles expressing CD62L and derived from activated leukocytes positively correlates with oxyhemoglobin desaturation index (ODI) whereas endothelial nitric oxide production correlated negatively with both CD62L+ microparticles and ODI. IH in mice induces early hemodynamic alterations and cardiovascular remodeling and systemic inflammation associated with overexpression of NF-kappaB, ICAM-1 and RANTES/CCL5 as well as T lymphocyte infiltration. Interestingly, we reported that although deletion of nmMLCK does not affect physiological cardiovascular parameters in vivo, it protects against endotoxic shock through the decrease of the up-regulation of NF-kappaB expression and activity, inducible nitric oxide synthase expression, and level of oxidative stress in the vascular media. nmMLCK deficiency or inhibition has been reported to attenuate systemic, lung and atherosclerotic inflammation. From these observations, one can advance the hypothesis that nmMLCK might be an attractive target to fight against the occurrence of inflammation and the vascular outcomes of OSA.
Objectives and aims: By combining basic research in animal models, molecular studies in different types of cell culture and biological and genetic analyses in humans, our aims are: (i) to validate the molecular implication of nmMLCK in IH-associated inflammation and vascular effects, (ii) to evaluate nmMLCK as a biological marker of the severity of OSA, and (iii) to analyze the association between nmMLCK polymorphism and OSA. The goal is to translate the knowledge on nmMLCK to the bedside in order to improve the management and treatment of patients of OSA.