Endothelial RAGE exacerbates acute postischaemic cardiac inflammation

Area of Science:

• Cardiovascular Research
• Immunology
• Molecular Medicine

Background:

• Advanced glycation end-products (AGEs) trigger inflammation via the receptor for AGEs (RAGE).
• RAGE plays a role in leukocyte adhesion and inflammatory responses following myocardial infarction (MI).
• Understanding RAGE's role is crucial for developing therapies against ischaemia-reperfusion injury.

Purpose of the Study:

• To investigate the role of RAGE in post-ischaemic leukocyte adhesion after myocardial infarction.
• To assess the impact of RAGE deficiency on myocardial function following ischaemia and reperfusion.
• To differentiate the contributions of endothelial and bone marrow-derived RAGE.

Main Methods:

• Utilized wildtype, ICAM-1-/-, RAGE-/-, and ICAM-1/RAGE-/- mice subjected to LAD-occlusion and reperfusion.
• Employed in vivo fluorescence microscopy to visualize leukocyte adhesion.
• Generated bone marrow chimeric mice to distinguish between endothelial and leukocyte RAGE.
• Performed invasive hemodynamic measurements, including left-ventricular developed pressure (LVDP).

Main Results:

• Combined deficiency of ICAM-1 and RAGE significantly reduced leukocyte retention in the infarcted myocardium.
• Neutrophil and monocyte infiltration were markedly decreased in ICAM-1/RAGE-/- mice.
• Chimeric mice studies indicated RAGE's pro-inflammatory role is primarily endothelial.
• Post-ischaemic LVDP was improved in mice lacking both ICAM-1 and RAGE.

Conclusions:

• Combined deficiency of ICAM-1 and RAGE effectively reduces leukocyte influx and improves cardiac function post-myocardial ischaemia.
• RAGE acts as a significant pro-inflammatory mediator in ischaemia-reperfusion injury.
• Targeting RAGE offers a potential therapeutic strategy for mitigating myocardial damage.