PI3Kγ Protects from Myocardial Ischemia and Reperfusion Injury through a Kinase-Independent Pathway

Background: PI3K gamma functions in the immune compartment to promote inflammation in response to G-protein-coupled receptor (GPCR) agonists and PI3K gamma also acts within the heart itself both as a negative regulator of cardiac contractility and as a pro-survival factor. Thus, PI3K gamma has the potential to both promote and limit M I/R injury. Methodology/Principal Findings: Complete PI3K gamma(-/-) mutant mice, catalytically inactive PI3K gamma(KD/KD) (KD) knock-in mice, and control wild type (WT) mice were subjected to in vivo myocardial ischemia and reperfusion (M I/R) injury. Additionally, bone-marrow chimeric mice were constructed to elucidate the contribution of the inflammatory response to cardiac damage. PI3K gamma(-/-) mice exhibited a significantly increased infarction size following reperfusion. Mechanistically, PI3K gamma is required for activation of the Reperfusion Injury Salvage Kinase (RISK) pathway (AKT/ERK1/2) and regulates phospholamban phosphorylation in the acute injury response. Using bone marrow chimeras, the cardioprotective role of PI3K gamma was mapped to non-haematopoietic cells. Importantly, this massive increase in M I/R injury in PI3K gamma(-/-) mice was rescued in PI3K gamma kinase-dead (PI3K gamma(KD/KD)) knock-in mice. However, PI3K gamma(KD/KD) mice exhibited a cardiac injury similar to wild type animals, suggesting that specific blockade of PI3K gamma catalytic activity has no beneficial effects. Conclusions/Significance: Our data show that PI3K gamma is cardioprotective during M I/R injury independent of its catalytic kinase activity and that loss of PI3K gamma function in the hematopoietic compartment does not affect disease outcome. Thus, clinical development of specific PI3K gamma blockers should proceed with caution.