Cardiac imaging using clinical 1.5 t MRI scanners in a murine ischemia/reperfusion model.

To perform cardiac imaging in mice without having to invest in expensive dedicated equipment, we adapted a clinical 1.5 Tesla (T) magnetic resonance imaging (MRI) scanner for use in a murine ischemia/reperfusion model. Phase-sensitive inversion recovery (PSIR) sequence facilitated the determination of infarct sizes in vivo by late gadolinium enhancement. Results were compared to histological infarct areas in mice after ischemia/reperfusion procedure with a good correlation (r = 0.807, P < .001). In addition, fractional area change (FAC) was assessed with single slice cine MRI and was matched to infarct size (r = -0.837) and fractional shortening (FS) measured with echocardiography (r = 0.860); both P < .001. Here, we demonstrate the use of clinical 1.5 MRI scanners as a feasible method for basic phenotyping in mice. These widely available scanners are capable of investigating in vivo infarct dimensions as well as assessment of cardiac functional parameters in mice with reasonable throughput.

PI3Kgamma protects from myocardial ischemia and reperfusion injury through a kinase-independent pathway.

BACKGROUND: PI3Kgamma functions in the immune compartment to promote inflammation in response to G-protein-coupled receptor (GPCR) agonists and PI3Kgamma also acts within the heart itself both as a negative regulator of cardiac contractility and as a pro-survival factor. Thus, PI3Kgamma has the potential to both promote and limit M I/R injury. METHODOLOGY/PRINCIPAL FINDINGS: Complete PI3Kgamma-/- mutant mice, catalytically inactive PI3KgammaKD/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. PI3Kgamma-/- mice exhibited a significantly increased infarction size following reperfusion. Mechanistically, PI3Kgamma 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 PI3Kgamma was mapped to non-haematopoietic cells. Importantly, this massive increase in M I/R injury in PI3Kgamma-/- mice was rescued in PI3Kgamma kinase-dead (PI3KgammaKD/KD) knock-in mice. However, PI3KgammaKD/KD mice exhibited a cardiac injury similar to wild type animals, suggesting that specific blockade of PI3Kgamma catalytic activity has no beneficial effects. CONCLUSIONS/SIGNIFICANCE: Our data show that PI3Kgamma is cardioprotective during M I/R injury independent of its catalytic kinase activity and that loss of PI3Kgamma function in the hematopoietic compartment does not affect disease outcome. Thus, clinical development of specific PI3Kgamma blockers should proceed with caution.