Phosphoinositide 3-kinase γ-deficient hearts are protected from the PAF-dependent depression of cardiac contractility

Alloatti, Giuseppe ; Levi, Renzo ; Malan, Daniela ; Del Sorbo, Lorenzo ; Bosco, Ornella ; Barberis, Laura ; Marcantoni, Andrea ; Bedendi, Ivano ; Penna, Claudia ; Azzolino, Ornella ; Altruda, Fiorella ; Wymann, Matthias ; Hirsch, Emilio ; Montrucchio, Giuseppe

In: Cardiovascular Research, 2003, vol. 60, no. 2, p. 242-249

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    Objectives: Following an ischemic insult, cardiac contractile recovery might be perturbed by the release of autacoids, like platelet-activating factor (PAF), that depress heart function by acting through G protein-coupled receptors (GPCRs). The signaling events downstream the PAF receptor that lead to the negative inotropic effect are still obscure. We thus investigated whether the GPCR-activated phosphoisositide 3-kinase γ (PI3Kγ) could play a role in the cardiac response to PAF. Methods: The negative inotropic effect of PAF was studied ex vivo, in isolated electrically driven atria and in Langendorff-perfused whole hearts derived from wild-type and PI3Kγ-null mice. Postischemic recovery of contractility was analyzed in normal and mutant whole hearts subjected to 30 min of ischemia and 40 min of reperfusion in the presence or absence of a PAF receptor antagonist. Results: While wild-type hearts stimulated with PAF showed increased nitric oxide (NO) production and a consequent decreased cardiac contractility, PI3Kγ-null hearts displayed reduced phosphorylation of nitric oxide synthase 3 (NOS3), blunted nitric oxide production and a complete protection from the PAF-induced negative inotropism. In addition, Langendorff-perfused PI3Kγ-null hearts showed a better contractile recovery after ischemia/reperfusion, a condition where PAF is known to be an important player in depressing contractility. In agreement with a role of PI3Kγ in this PAF-mediated signaling, postischemic contractile recovery in PI3Kγ-null mice appeared overlapping with that of normal hearts treated with the PAF receptor antagonist WEB 2170. Conclusion: These data indicate a novel PAF-dependent signaling pathway that, involving PI3Kγ and NOS3, contributes to postischemic contractile depression