PSAP protects against acute myocardial ischemia-reperfusion injury by rescuing ASAH1 expression to accelerate ceramide degradation and attenuate cardiomyocyte apoptosis.
PSAP expression was significantly downregulated in heart tissue subjected to acute ischemia-reperfusion surgery.
AAV9-mediated PSAP overexpression in vivo significantly reduced infarct size and attenuated cardiomyocyte apoptosis following I/R injury.
PSAP overexpression in OGD/R-treated primary neonatal rat cardiomyocytes (NRCMs) decreased apoptosis, while PSAP knockdown exacerbated apoptosis.
PSAP mechanistically accelerates ceramide degradation by rescuing expression of the lysosomal enzyme ASAH1 (N-acylsphingosine amidohydrolase 1).
PSAP overexpression attenuated I/R-induced ceramide accumulation in cardiomyocytes.
This research suggests that a protein called prosaposin (PSAP), found in cellular compartments called lysosomes, plays an important protective role in the heart during ischemia-reperfusion (I/R) injury — the damage that occurs when blood flow is restored to heart tissue after a blockage. The researchers found that PSAP levels drop significantly during I/R injury, and that artificially restoring PSAP — either by gene therapy in live animals or by genetic manipulation in heart cells grown in the lab — reduced the amount of heart tissue that died and decreased programmed cell death (apoptosis) in heart muscle cells. The study also uncovered how PSAP provides this protection. It works by maintaining the activity of another lysosomal protein called ASAH1, which is responsible for breaking down a fat molecule called ceramide. When I/R injury occurs, ASAH1 levels fall, ceramide builds up inside heart cells, and this buildup triggers cell death. PSAP essentially acts as a guardian that keeps ASAH1 functioning, preventing toxic ceramide accumulation and protecting heart cells from dying. This research suggests that the PSAP-ASAH1-ceramide pathway is a previously unrecognized mechanism underlying heart cell death during heart attacks, and that targeting PSAP could be a new therapeutic strategy for reducing heart damage in patients who experience myocardial infarction and undergo reperfusion therapy (such as angioplasty or clot-busting drugs).
Chen Y, Ye X, Zha C, Jin C, Chen H, Wang H, et al.. (2026). PSAP Protects Against Acute Myocardial Ischemia-Reperfusion Injury by Promoting ASAH1-Mediated Ceramide Metabolism.. Journal of cardiovascular translational research. https://doi.org/10.1007/s12265-026-10779-3