Abstract Body: Introduction: Complications after acute myocardial infarction are among the leading causes of mortality in the United States. Ischemia-reperfusion injury occurs after reperfusion which induces more damage to the heart despite the return of blood flow, which can lead to heart failure. Previous work has identified low-density lipoprotein receptor-related protein 1, or LRP1, as a potential therapeutic target to protect cell death from reperfusion injury. In this work, an apoptosis model was expanded to predict the signaling effects of an LRP1 agonist during ischemia.

Methods: LRP1 agonist was added as an input to an existing cardiomyocyte apoptosis network to predict LRP1 activity and its effects on cell death during ischemia. New reactions of LRP1 with PKC, Shp2, Shc1, and Src were added for more detail upstream. The model was validated using adult mouse cardiomyocytes with ischemia and reperfusion. SP16, a synthetic LRP1 agonist drug, was delivered to measure outputs such as Akt phosphorylation, caspase3, and apoptosis.

Results: LRP1 activation increased Ras/PI3K/Akt and MEK/ERK pathway activity, which is part of the reperfusion-injury salvage kinase (RISK) pathway. Outputs of the model such as apoptosis and cell death were decreased due to LRP1 agonist activity. The model predictions were then validated against the experiments, with 7 out of 8 model predictions (88%) validated.

Conclusions: The cardiomyocyte apoptosis model was able to accurately predict pathways by which LRP1 prevents cell death, main pathways involved in LRP1 signaling such as the RISK pathway. This work supports LRP1 as a potential therapeutic target to induce pro-survival signaling in the heart during ischemia-reperfusion.