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)

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
149 Downloads (Pure)


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
Issue number16
Publication statusPublished - 11 Aug 2021


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

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry


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