Phosphoinositide 3-kinase gamma-deficient hearts are protected from the PAF-dependent depression of cardiac contractility.
OBJECTIVE
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 gamma (PI3Kgamma) 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 PI3Kgamma-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, PI3Kgamma-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 PI3Kgamma-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 PI3Kgamma in this PAF-mediated signaling, postischemic contractile recovery in PI3Kgamma-null mice appeared overlapping with that of normal hearts treated with the PAF receptor antagonist WEB 2170.


CONCLUSIONS
These data indicate a novel PAF-dependent signaling pathway that, involving PI3Kgamma and NOS3, contributes to postischemic contractile depression.
Alloatti
Giuseppe
G
Dipartimento di Biologia Animale e dell'Uomo e Istituto Nazionale per la Fisica della Materia, Università di Torino, 10123 Torino, Italy.
Levi
Renzo
R
Malan
Daniela
D
Del Sorbo
Lorenzo
L
Bosco
Ornella
O
Barberis
Laura
L
Marcantoni
Andrea
A
Bedendi
Ivano
I
Penna
Claudia
C
Azzolino
Ornella
O
Altruda
Fiorella
F
Wymann
Matthias
M
Hirsch
Emilio
E
Montrucchio
Giuseppe
G
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D058544:Class Ib Phosphatidylinositol 3-Kinase; D005260:Female; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010477:Perfusion; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010972:Platelet Activating Factor / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D001381:Azepines; D007527:Isoenzymes; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C063964:bepafant; D019001:Nitric Oxide Synthase; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D019331:NG-Nitroarginine Methyl Ester