Extracellular RIPK3 Acts as a Damage-Associated Molecular Pattern to Exaggerate Cardiac Ischemia/Reperfusion Injury

Area of Science:

• Cardiology
• Molecular Biology
• Immunology

Background:

• Cardiac ischemia/reperfusion (I/R) injury is a significant clinical challenge with no effective therapies.
• Damage-associated molecular patterns (DAMPs) contribute to inflammation and injury following cellular damage.
• Receptor-interacting protein kinase 3 (RIPK3) is known for its role in necroptosis and as a biomarker, but its function in cardiac I/R injury is unexplored.

Purpose of the Study:

• To investigate the role of extracellular RIPK3 in cardiac I/R injury.
• To determine if plasma RIPK3 levels correlate with outcomes in patients undergoing percutaneous coronary intervention (PCI).
• To elucidate the underlying mechanisms of RIPK3's action in cardiac I/R injury.

Main Methods:

• Analysis of plasma RIPK3 levels in patients with acute myocardial infarction undergoing PCI (discovery and validation cohorts).
• In vitro studies using neonatal rat ventricular myocytes, macrophages, and endothelial cells.
• In vivo studies using mouse models of myocardial I/R injury.
• Investigation of RIPK3-RAGE-CaMKII signaling pathways.

Main Results:

• Elevated plasma RIPK3 post-PCI is associated with poorer short- and long-term outcomes in myocardial infarction patients.
• Recombinant RIPK3 exacerbated I/R injury in cell and animal models, while a RIPK3 antibody alleviated it.
• RIPK3 acts as a DAMP, binding to RAGE and activating CaMKII, leading to detrimental effects.

Conclusions:

• Plasma RIPK3 concentration is a predictor of adverse cardiovascular events in patients with acute myocardial infarction undergoing PCI.
• Extracellular RIPK3 causally contributes to cardiac I/R injury through RAGE/CaMKII signaling.
• RIPK3 represents a promising therapeutic target for myocardial I/R injury and its complications.