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.
Siragusa M, Katare R, Meloni M, Damilano F, Hirsch E, Emanueli C, Madeddu P. Involvement of phosphoinositide 3-kinase gamma in angiogenesis and healing of experimental myocardial infarction in mice. Circ Res. 2010; 106: 757–768.
Curcio A, Noma T, Naga Prasad SV, Wolf MJ, Lemaire A, Perrino C, Mao L, Rockman HA. Competitive displacement of phosphoinositide 3-kinase from beta-adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling. Am J Physiol Heart Circ Physiol. 2006; 291: H1754–H1760.