Background: PI3Kγ functions in the immune compartment to promote inflammation in response to G-protein-coupled receptor (GPCR) agonists and PI3Kγ also acts within the heart itself both as a negative regulator of cardiac contractility and as a pro-survival factor. Thus, PI3Kγ has the potential to both promote and limit M I/R injury. Methodology/Principal Findings: Complete PI3Kγ-/- mutant mice, catalytically inactive PI3KγKD/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, bonemarrow chimeric mice were constructed to elucidate the contribution of the inflammatory response to cardiac damage. PI3Kγ-/- mice exhibited a significantly increased infarction size following reperfusion. Mechanistically, PI3Kγ 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 PI3Kγ was mapped to non-haematopoietic cells. Importantly, this massive increase in M I/R injury in PI3Kγ-/- mice was rescued in PI3Kc kinase-dead (PI3KγKD/KD) knock-in mice. However, PI3Kγ KD/KD mice exhibited a cardiac injury similar to wild type animals, suggesting that specific blockade of PI3KPI3KγKD/KD catalytic activity has no beneficial effects. Conclusions/Significance: Our data show that PI3KPI3KγKD/KD is cardioprotective during M I/R injury independent of its catalytic kinase activity and that loss of PI3KPI3KγKD/KD function in the hematopoietic compartment does not affect disease outcome. Thus, clinical development of specific PI3KPI3KγKD/KD blockers should proceed with caution.
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