Abstract P1040: The Protective Effects Of Sialidase Neu3 Against Cardiac Ischemia And Reperfusion Injury

The salvage of myocardium after acute myocardial infarction (AMI) can only be achieved by timely reperfusion. This is life-saving, however it may also lead to additional damage in the form of ischemia and reperfusion injury (IRI). Protecting cardiac tissue from IRI remains one of the greatest unmet clinical needs in cardiology. Therefore, a better understanding of IRI pathophysiology is necessary. There has been increasing recognition that the activation of specific molecular mechanisms, including the Reperfusion Injury Salvage Kinase (RISK) pathway and HIF-1α contributes to cardioprotection against IRI. Along this line, we previously reported that sialidase Neu3, which removes sialic acid from glycosphingolipids, controls HIF-1α activation via a prolyl hydroxylase-independent pathway. In fact, we found that Neu3 was up-regulated under chronic hypoxia in cyanotic congenital cardiac patients and its overexpression increased muscle cells’ resistance to hypoxic stress by activating the RISK pathway. In light of these premises, the goal of this study was to determine Neu3's involvement in the cardiac response to IRI and establish whether its inducible activation could promote cardioprotection. An IRI model in mice, obtained by temporarily blocking the LAD coronary artery, showed that Neu3 is modulated during this process. Notably, Neu3 showed progressive downregulation during the ischemic phase followed by its reactivation during reperfusion. These results were similar to the Neu3 modulation we observed in human cardiac cells (AC16) exposed to an IRI model in vitro . The overexpression of Neu3 during ischemia had beneficial effects both in terms of cell proliferation and reduction of oxidative stress after reperfusion. We found that Neu3 promotes the activation of glycolytic enzymes during the ischemic phase as well as the maintenance of the mitochondrial membrane potential, suggesting that the Neu3-overexpressing human cardiomyocyte undergoes more aerobic metabolism even in oxygen-deficient environments. In conclusion, these results support a role for Neu3 in cardioprotection against IRI, suggesting that it may be a useful therapeutic target for improving the recovery of patients who have undergone acute myocardial infarction.