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

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.

• Authors: Naveed Akbar, Calum Forteath, Muhammad S Hussain, Kathleen Reyskens, Jill J F Belch, Chim C Lang, Ify R Mordi, U Bhalraam, J Simon C Arthur, Faisel Khan
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 16 (Aug 11 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34445361 (Publication Type: Journal Article)

Chemical References

• RPS6KA4 protein, human
• Ribosomal Protein S6 Kinases, 90-kDa
• mitogen and stress-activated protein kinase 1

Topics

• Adult
• Aged
• Animals
• Case-Control Studies
• Cells, Cultured
• Cohort Studies
• Endothelium, Vascular (physiopathology)
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Ribosomal Protein S6 Kinases, 90-kDa (genetics, physiology)
• Signal Transduction (physiology)
• Vascular Diseases (genetics, physiopathology)
• Young Adult