The inhibition of Prolyl Endopeptidase as a potential therapeutic target for the treatment of ischemic-reperfusion

Ischemia/reperfusion injury (IRI) is a complex pathophysiological process characterized by disturbances in blood circulation caused by various factors, such as traumatic shock, surgery, organ transplantation and thrombus. Severe metabolic dysregulation and destruction of tissue structure are observed after restoration of blood flow to ischemic tissue. The heart and kidneys, being highly perfused organs, are very susceptible to ischemic and subsequent reperfusion injury. The incidence of myocardial and renal IRI has a high morbidity and mortality rate. Several studies have shown that among the mechanisms involved in the pathophysiology of IRI are inflammation, apoptosis and angiogenesis. Recently, the involvement of prolyl endopepetidase (PREP) in inflammatory response and angiogenesis has been demonstrated. Therefore, the aim of this PhD project is to investigate the effects of a selective PREP inhibitor, KYP-2047, in the regulation of inflammation, apoptosis and angiogenesis, in in vivo models of myocardial ischemia reperfusion (MI/R) and kidney ischemia/reperfusion (KI/R). Myocardial I/R was induced by coronary artery occlusion (15 minutes) followed by reperfusion, whereas kidney I/R was induced by renal artery occlusion (30 minutes), followed by reperfusion. The mice were pre-treated intraperitoneally with KYP-2047 at doses of 2.5 and 5 mg/kg in cardiac ischemia and treated at doses of 0.5, 1, and 5 mg/kg in renal ischemia. Hearts and kidneys were removed and processed for histological, immunohistochemical and biomolecular analysis. Inhibition of PREP, through KYP-2047, reduced histological damage, neutrophil accumulation and inflammation in both models. In addition, KYP-2047 was able to modulate angiogenesis and reduce apoptosis in renal and cardiac context. This protective effect of KYP-2047 could be related to the modulation of NF-κB and MAPK pathways in MI/R injury and to the activation of PP2A in KI7R injury. Therefore, these results demonstrated the protective effect of KYP-2047, highlighting the role of PREP inhibition in cardiac and renal ischemia, suggesting PREP as a therapeutic target for MI/R and KI/R injury.