Effects of PI3Kγ Inhibition Using AS-605240 in Acute Myocardial Infarction

To the Editor:

We read with interest the article by Siragusa et al¹ showing a protective effect of phosphoinositide-3 kinase (PI3K)γ in experimental myocardial infarction in mice. The authors describe impaired neovascularization in mice with genetic deletion of PI3Kγ (PI3Kγ KO) leading to significantly worse remodeling versus wild-type (WT) mice. The authors also show that pharmacological inhibition with AS-605240 (started 3 days before infarction) led to a phenotype similar to PI3Kγ KO mice. However, mice expressing catalytically inactive PI3Kγ (PI3Kγ KD) did not show worse remodeling than WT, and actually showed a trend toward improved function (left ventricular fractional shortening, 21% in the PI3Kγ KD versus 17% in the WT and 12% in the PI3Kγ KO), arguing that the beneficial effects of PI3Kγ are more likely to be kinase-independent. This is in agreement with previous studies involving PI3Kγ KO mice² and a recent study by Haubner et al in PI3Kγ KO and KD mice.³ The inconsistency between the PI3Kγ KD mice (in which the kinase activity is lost) and the mice treated with AS-605240 (a kinase inhibitor) is not adequately addressed in the article¹ and is particularly disturbing because it raises the question that the effects of AS-605240 may have been, at least in part, independent of the inhibition of PI3Kγ kinase activity.