The novel sphingosine-1-phosphate receptor modulator KRP-203 prevents myocardial ischemia-reperfusion injury by preserving mitochondrial function through activation of the RISK and SAFE signaling pathways.

KRP-203, a novel agonist of sphingosine-1-phosphate receptors (S1PRs), has shown promise in treating in immune-related diseases by blocking lymphocyte recruitment to inflamed tissues. Although S1PRs are abundantly expressed in cardiomyocytes, the specific effects of KRP-203 on these cells remain poorly understood. Here, we investigated the impact and mechanisms of KRP-203 pretreatment on myocardial ischemia-reperfusion injury (MIRI) via its interaction with cardiomyocyte S1PRs. To evaluate the efficacy of KRP-203 administered before ischemia, three MIRI models (in vivo, ex vivo, and in vitro) were employed. Overall, KRP-203 pretreatment significantly improved left ventricular systolic function, lowered serum levels of creatine kinase MB isoenzyme and lactate dehydrogenase, mitigated myocardial histopathological damage, and reduced both infarct size and cardiomyocyte apoptosis in vivo. Similar protective effects were observed in the in vitro and ex vivo models. Additionally, KRP-203 was found to preferentially bind to S1PR1 over S1PR2 and S1PR3 in cardiomyocytes. Further analysis revealed that pretreatment with KRP-203 significantly lowered the concentration of reactive oxygen species (ROS), prevented mitochondrial permeability transition pore opening, boosted mitochondrial membrane potential (MMP), and increased phosphorylation of AKT, EKR, GSK-3β, JAK2, and STAT3. These effects were reversed by S1PR1 knockdown in cardiomyocytes. Moreover, knocking down S1PR1 in the heart abrogated the cardioprotective effects of KRP-203. In summary, the findings indicate that KRP-203 pretreatment alleviates MIRI independently of lymphocyte involvement. Mechanistically, KRP-203 selectively activates S1PR1 on cardiomyocytes, triggering the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways to maintain mitochondrial integrity. These findings provide fresh perspectives on the pharmacological properties of KRP-203.