Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction

Naveed Akbar (Lead / Corresponding author), Calum Forteath, Muhammad Hussain, Kathleen Reyskens, Jill J. F. Belch, Chim C. Lang, Ify Mordi, U Bhalraam, J. Simon C. Arthur, Faisel Khan (Lead / Corresponding author)

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Abstract

Inflammation promotes endothelial dysfunction but the underlying mechanisms remain poorly defined in vivo. 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 mice 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. Activation of MSK1/2 could reduce pro-inflammatory responses and preserve endothelial vasodilator function before development of significant vascular disease
Original languageEnglish
Article number8655
Number of pages22
JournalInternational Journal of Molecular Sciences
Volume22
Issue number16
DOIs
Publication statusPublished - 11 Aug 2021

Keywords

  • Endothelium
  • Vascular Biology
  • Vascular Disease
  • MAPK
  • Cytokine
  • Vascular disease
  • Vascular biology

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