PSAP Protects Against Acute Myocardial Ischemia-Reperfusion Injury by Promoting ASAH1-Mediated Ceramide Metabolism

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cellular Physiology

Background:

• Myocardial ischemia-reperfusion (I/R) injury is a major cause of heart disease with limited effective treatments.
• The molecular mechanisms underlying I/R injury, particularly ceramide metabolism and cardiomyocyte apoptosis, require further elucidation.

Purpose of the Study:

• To investigate the role of lysosomal prosaposin (PSAP) in regulating ceramide homeostasis.
• To determine the downstream mechanisms of PSAP in cardiomyocyte apoptosis during acute I/R injury.
• To assess the therapeutic potential of PSAP for myocardial I/R injury.

Main Methods:

• Assessed PSAP expression in myocardial tissue after I/R surgery.
• Utilized adeno-associated virus serotype 9 (AAV9) for in vivo PSAP overexpression (PSAP-OE).
• Investigated PSAP's effect on apoptosis and ceramide levels in primary cardiomyocytes under oxygen-glucose deprivation/reperfusion (OGD/R) conditions.
• Examined the impact of PSAP on N-acylsphingosine amidohydrolase 1 (ASAH1) expression.

Main Results:

• PSAP expression was significantly decreased in hearts subjected to I/R.
• In vivo AAV9-PSAP-OE reduced infarct size and cardiomyocyte apoptosis post-I/R.
• PSAP overexpression protected cardiomyocytes from OGD/R-induced apoptosis, while PSAP knockdown worsened it.
• PSAP enhanced ceramide degradation by upregulating lysosomal ASAH1, mitigating ceramide accumulation and cell death.

Conclusions:

• PSAP plays a critical protective role in acute myocardial I/R injury.
• PSAP regulates ceramide homeostasis by modulating the ASAH1-mediated degradation pathway.
• PSAP represents a promising therapeutic target for mitigating myocardial I/R injury and associated cardiomyocyte apoptosis.