We sought to determine whether Gab1 plays a role in cardioprotection against I/R injury and if so,to investigate the underlying mechanism.Cardiomyocyte-specific Gab1 knockout (CGKO) mice exhibited increased infarct size and decreased cardiac function after I/R injury compared with control mice.Consistently,in hearts of CGKO mice subjected to I/R,the activation of caspase 3 and myocardial apoptosis were markedly enhanced whereas the activation of Akt and MAPK was attenuated.The effects of Gab1 against I/R injury were recapitulated in isolated adult cardiomyocytes following exposure to oxidant hydrogen peroxide.Interestingly,oxidative stress induced a significant interaction between Gab1 and the ErbB2/4 receptors.Inhibition of ErbB kinase activity suppressed the phosphorylation of Gab1and the activation of both MAPK and Akt,accompanied by an increase in cell death of cardiomyocytes exposed to hydrogen peroxide.Our results suggest that Gabl is essential for cardioprotection against IR oxidative injury via coordinating signals from ErbB receptors to both MAPK and Akt pathways.