PI3Kγ protects from myocardial ischemia and reperfusion injury through a kinase-independent pathway

Bernhard J. Haubner, G. Gregory Neely, Jakob G.J. Voelkl, Federico Damilano, Keiji Kuba, Yumiko Imai, Vukoslav Komnenovic, Agnes Mayr, Otmar Pachinger, Emilio Hirsch, Josef M. Penninger, Bernhard Metzler

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere9350
JournalPloS one
Volume5
Issue number2
DOIs
Publication statusPublished - Feb 22 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

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