Abstract Body: Coronary reperfusion restores blood flow after acute myocardial infarction, but also triggers ischemia-reperfusion injury (IRI), which exacerbates tissue damage and promotes heart failure. Despite the urgent need for cardioprotective strategies, none have been successfully translated into clinical practice, highlighting the importance of deeply understanding the pathophysiology of IRI. In this context, our group has previously demonstrated that the sialidase Neu3, which removes sialic acid from glycosphingolipids, is modulated during IRI in vivo and that its overexpression in rat cardiomyoblasts protects against IRI via the reperfusion injury salvage kinase (RISK) and HIF-1α pathways activation. Therefore, this study aims to further elucidate the cardioprotective role of Neu3 by developing an inducible, cardiac-specific mouse model for Neu3 overexpression.
Inducible cardiac-specific Neu3-overexpressing mice (αMHC-Cre/LSL-Neu3) were generated by crossing a tamoxifen-inducible α-MHC-Cre mouse with a transgenic mouse carrying a floxed transcriptional STOP sequence upstream of the Neu3 gene.
Tamoxifen-treated αMHC-Cre/LSL-Neu3 mice showed significant Neu3 overexpression with reduced sialic acid levels in cardiomyocytes measured with specific lectins. No appreciable differences in cardiac morphology or functionality were observed between these mice and their wild-type counterparts. However, after surgical induction of IRI, the αMHC-Cre/LSL-Neu3 mice showed a significant reduction in infarct size as determined by Evans blue/TTC double staining, accompanied by improved cardiac functionality.
Possible molecular mechanisms underlying the observed effects were investigated by proteomic analysis of the damaged cardiac tissue. The analyses indicate that Neu3 attenuates inflammatory responses, preserves the mechanical and contractile properties of the heart and improves the structural integrity of cardiac tissue.
These results suggest that sialidase Neu3 is a promising target to promote cardioprotection and reduce the severity of myocardial infarction.