Therapeutic effect of SP‐8356 on pulmonary embolism‐associated cardiac injury is mediated by its ability to suppress apoptosis and inflammation

The cyclophilin A–CD147 interaction has been reported to be one of the most potential therapeutic targets for the treatment of acute pulmonary embolism. The signalling of extracellular signal‐regulated kinase 1/2 (ERK1/2) was also reported in the pathogenesis of cardiac injury. Since SP‐8356 is regarded as a novel Inhibitor of CD147‐Cyclophilin, the study aimed to evaluate potential therapeutic effects of SP‐8356 for pulmonary embolism‐associated cardiac injury. Western blot and immunohistochemistry were carried out to analyse the expression of MMP‐9, ERK1/2, phosphorylated ERK1/2 (p‐ERK1/2), P65, p‐P65, and CyA protein in PE cell and rat models under distinct conditions. Flow cytometry and TUNEL were carried out to examine the apoptosis of primary rat myocardiocytes and PE rat models under distinct conditions. CyA treatment on primary rat myocardiocytes remarkably raised the expression of MMP‐9, p‐ERK1/2 and p‐P65 protein expression; SP8536 treatment effectively restored the CyA‐induced up‐regulation of MMP‐9, p‐ERK1/2 and p‐P65 protein expression in primary rat myocardiocytes. Besides, flow cytometry analysis showed that SP8536 remarkably suppressed the CyA‐induced elevation of cell apoptosis rate of primary rat myocardiocytes. Moreover, SP8536 notably diminished the abnormal elevation of right ventricular systolic pressure (RVSP), Troponin I and Myeloperoxidase activity in PE rat models. Furthermore, SP‐8536 significantly restored the up‐regulation of MMP‐9, p‐ERK1/2, p‐P65, CyA protein and the cellular apoptosis in the PE rat model. Our study validated that SP‐8356 could suppress cell apoptosis and inflammatory response via down‐regulating the highly expressed MMP‐9, p‐ERK1/2, and p‐P65 and MMP‐9 in PE‐associated cardiac injury in a dose‐dependent manner.