Sialidase Neu3: A Novel Cardioprotective Target Against Ischemia And Reperfusion Injury

Coronary reperfusion techniques are life-saving approaches to restore blood flow to cardiac tissue after acute myocardial infarction. However, they also lead to what is known as ischemia and reperfusion injury (IRI), which causes additional damage and heart failure. Despite the urgent need for cardioprotective strategies against IRI, none has yet been introduced into clinical practice, suggesting that a more detailed characterization of the molecular mechanisms underlying the pathogenesis of IRI is essential. In this regard, our research group has shown that sialidase Neu3, an enzyme responsible for removing sialic acid from glycosphingolipids, is modulated during IRI in vivo and that its constitutive overexpression in rat cardiomyoblasts is sufficient to counteract the deleterious effects of IRI through activation of reperfusion injury salvage kinase (RISK) and the HIF-1α pathway. Thus, in this study, we developed an inducible model of Neu3 overexpression in human cardiac cells (AC16) and in mice to further elucidate the role of this protein in promoting cardioprotection. Inducible upregulation of Neu3 significantly increased cell resistance and reduced oxidative stress in AC16 exposed to IRI in vitro. These beneficial effects were related to Neu3-mediated maintenance of mitochondrial membrane potential, which was altered in control cells. Moreover, RNAseq data showed that Neu3 activation was associated with upregulation of the cellular responses to stress, whereas, in contrast, the pro-inflammatory signaling pathways of TNF-α and IL-22 were downregulated. We also generated αMHC-Cre/LSL-Neu3 mice for the first time by crossing the tamoxifen-inducible αMHC-Cre mouse with a mouse carrying a floxed-transcriptional STOP sequence upstream of Neu3. These mice were characterized for cardiac morphology and functionality and showed no significant differences compared with wild-type mice. They will undergo surgical induction of IRI to test the beneficial effects of Neu3. Based on our findings, it can be hypothesized that Neu3 plays a significant role in the cardiac response to IRI. Consequently, targeting Neu3 may hold therapeutic promise in increasing cardioprotection and mitigating the incidence and severity of myocardial infarction.