Abstract 880: The Role of Sialidase Neu3 in the Cardiac Response to Ischemia and Reperfusion Injury

Abstract

Reperfusion strategies are life-saving approaches to restore the blood flow in the cardiac tissue after acute myocardial infarction (AMI). However, they come with the drawback that they inevitably induce ischemia/reperfusion injury (IRI), resulting in increased cardiomyocytes damage and heart failure. In this context, the physiological activation of several pro-survival kinases, such as Akt and Erk, as well as of the hypoxia inducible factor (HIF) has been recognized to be critical during IRI. Along with this line, we recently discovered a novel, PHDs independent, mechanism of HIF-1; activation mediated by sialidase Neu3. Interestingly, Neu3 is upregulated under chronic hypoxia in cyanotic congenital cardiac patients. Moreover, induced activation of Neu3 increased myoblast resistance to hypoxic stress. Thus, in this study, we further investigated the possible role of Neu3 in protecting cardiac myoblasts during IRI. In particular, we set-up an in-vitro model of IRI on H9C2 rat cardiomyoblasts. Results showed a modulation of Neu3 during IRI, with a progressive down-regulation during the ischemic phase, followed by a reactivation during the reperfusion phase. Remarkably, overexpression of Neu3 significantly increased cardiomyoblasts resistance to IRI, both in terms of cell proliferation and resistance to apoptosis. Treatment with Akt and Erk inhibitors, as well as with a Neu3 specific inhibitor completely reverted the beneficial effects mediated by Neu3 upregulation. In conclusion, our results show that Neu3 activation has a cardioprotective effect during IRI, calling for further studies to unveil its full potential as a therapeutic target to treat cardiac ischemia and reperfusion injury and to improve patients recover after AMI.