1. Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction
- Author
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Naveed Akbar, Kathleen M. S. E. Reyskens, Muhammad S. Hussain, Ify R. Mordi, Calum Forteath, J. S. C. Arthur, U Bhalraam, Chim C. Lang, Faisel Khan, and Jill J. F. Belch
- Subjects
MAPK/ERK pathway ,Male ,medicine.medical_treatment ,Vasodilation ,Cohort Studies ,chemistry.chemical_compound ,Mice ,cytokine ,Medicine ,Biology (General) ,Endothelial dysfunction ,Receptor ,Spectroscopy ,Cells, Cultured ,Mice, Knockout ,biology ,Kinase ,vascular disease ,General Medicine ,Middle Aged ,Computer Science Applications ,Chemistry ,medicine.anatomical_structure ,Cytokine ,Mitogen-activated protein kinase ,Female ,medicine.symptom ,Proto-oncogene tyrosine-protein kinase Src ,Signal Transduction ,Adult ,medicine.medical_specialty ,Endothelium ,endothelium ,QH301-705.5 ,Inflammation ,Ribosomal Protein S6 Kinases, 90-kDa ,Catalysis ,Article ,Nitric oxide ,Inorganic Chemistry ,Young Adult ,Internal medicine ,Animals ,Humans ,Vascular Diseases ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Aged ,business.industry ,Vascular disease ,Organic Chemistry ,vascular biology ,medicine.disease ,MAPK ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Case-Control Studies ,biology.protein ,Endothelium, Vascular ,business - Abstract
Inflammation promotes endothelial dysfunction. Using translational vascular function testing in myocardial Infarction patients, a situation where inflammation is prevalent, and knock-out (KO) mouse models we demonstrate a role for mitogen-activated-protein-kinases (MAPKs) in endothelial dysfunction. Myocardial infarction significantly lowers mitogen and stress kinase 1/2 (MSK1/2) expression in peripheral blood mononuclear cells and diminished endothelial function. To further understand the role of MSK1/2 in vascular function we developed in vivo animal models to assess vascular responses to vasoactive drugs using laser Doppler imaging. Genetic deficiency of MSK1/2 in mice increased plasma levels of pro-inflammatory cytokines and promoted endothelial dysfunction, through attenuated production of nitric oxide (NO), which were further exacerbated by cholesterol feeding. MSK1/2 are activated by toll-like receptors through MyD88. MyD88 KO showed preserved endothelial function and reduced plasma cytokine expression, despite significant hypercholesterolemia. MSK1/2 kinases interact with MAPK-activated proteins 2/3 (MAPKAP2/3), which limit cytokine synthesis. Cholesterol-fed MAPKAP2/3 KO mice showed reduced plasma cytokine expression and preservation of endothelial function. MSK1/2 plays a significant role in the development of endothelial dysfunction and may provide a novel target for intervention to reduce vascular inflammation. Selective activation of MSK1/2 could reduce pro-inflammatory responses and preserve endothelial function before development of significant vascular disease.Graphical Abstract
- Published
- 2021
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