Here, taking advantage of the physiological characteristics of the GSK3β kinase in the cardioprotection field, and combining in silico analysis with in vitro and in vivo genetic approaches, we report serine 663 phosphorylation as a physiological and clinical event in the SERCA2 regulation in heart, and that its limitation improves cardiomyocyte function and prevents cell death and subsequent myocardial infarct size. Here, ATP2A2 is linked to myocardial infarction.