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Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction
- Source :
- International Journal of Molecular Sciences, Volume 22, Issue 16, International Journal of Molecular Sciences, Vol 22, Iss 8655, p 8655 (2021)
- Publication Year :
- 2021
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2021.
-
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
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....f7f1987509dcb1be76732681b13f7318
- Full Text :
- https://doi.org/10.3390/ijms22168655