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

Area of Science:

• Cardiovascular Biology
• Inflammation and Immunology
• Molecular Medicine

Background:

• Endothelial dysfunction is a hallmark of cardiovascular disease, often driven by inflammation.
• The precise molecular mechanisms linking inflammation to endothelial dysfunction in vivo are not fully understood.
• Myocardial infarction (MI) is a condition associated with significant inflammation and endothelial dysfunction.

Purpose of the Study:

• To investigate the role of mitogen-activated-protein-kinases (MAPKs) in inflammation-induced endothelial dysfunction.
• To elucidate the specific involvement of mitogen and stress-activated protein kinase 1/2 (MSK1/2) in vascular function.
• To identify potential therapeutic targets for reducing vascular inflammation and preserving endothelial health.

Main Methods:

• Translational vascular function testing in myocardial infarction patients.
• Development and utilization of knock-out (KO) mouse models lacking MSK1/2, MyD88, or MAPKAP2/3.
• In vivo assessment of vascular responses using laser Doppler imaging and measurement of plasma cytokine levels.

Main Results:

• Myocardial infarction reduced MSK1/2 expression and impaired endothelial function in patients.
• MSK1/2 deficiency in mice led to increased pro-inflammatory cytokines, endothelial dysfunction, and reduced nitric oxide (NO) production.
• MyD88 and MAPKAP2/3 knock-out mice exhibited preserved endothelial function and reduced inflammation, even under hypercholesterolemic conditions.

Conclusions:

• Mitogen-activated-protein-kinases, particularly MSK1/2, play a critical role in the development of endothelial dysfunction.
• The MSK1/2 pathway, activated via toll-like receptors and MyD88, influences nitric oxide production and inflammatory responses.
• Targeting MSK1/2 activation presents a potential therapeutic strategy to mitigate vascular inflammation and improve endothelial function.