Distinct effects of leukocyte and cardiac phosphoinositide 3-kinase γ activity in pressure overload-induced cardiac failure.
BACKGROUND
Signaling from phosphoinositide 3-kinase γ (PI3Kγ) is crucial for leukocyte recruitment and inflammation but also contributes to cardiac maladaptive remodeling. To better understand the translational potential of these findings, this study investigates the role of PI3Kγ activity in pressure overload-induced heart failure, addressing the distinct contributions of bone marrow-derived and cardiac cells.


RESULTS
After transverse aortic constriction, mice knock-in for a catalytically inactive PI3Kγ (PI3Kγ KD) showed reduced fibrosis and normalized cardiac function up to 16 weeks. Accordingly, treatment with a selective PI3Kγ inhibitor prevented transverse aortic constriction-induced fibrosis. To define the cell types involved in this protection, bone marrow chimeras, lacking kinase activity in the immune system or the heart, were studied after transverse aortic constriction. Bone marrow-derived cells from PI3Kγ KD mice were not recruited to wild-type hearts, thus preventing fibrosis and preserving diastolic function. After prolonged pressure overload, chimeras with PI3Kγ KD bone marrow-derived cells showed slower development of left ventricular dilation and higher fractional shortening than controls. Conversely, in the presence of a wild-type immune system, KD hearts displayed bone marrow-derived cell infiltration and fibrosis at early stages but reduced left ventricular dilation and preserved contractile function at later time points.


CONCLUSIONS
Together, these data demonstrate that, in response to transverse aortic constriction, PI3Kγ contributes to maladaptive remodeling at multiple levels by modulating both cardiac and immune cell functions.
Department of Genetics, Biology, and Biochemistry, University of Torino, Torino, Italy.
Federico
F
Damilano
Irene
I
Franco
Cinzia
C
Perrino
Katrin
K
Schaefer
Ornella
O
Azzolino
Daniela
D
Carnevale
Giuseppe
G
Cifelli
Pierluigi
P
Carullo
Riccardo
R
Ragona
Alessandra
A
Ghigo
Alessia
A
Perino
Giuseppe
G
Lembo
Emilio
E
Hirsch
D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis / Q000235:genetics; D055879:Gene Knock-In Techniques; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics; D007962:Leukocytes / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology*; D020257:Ventricular Remodeling / Q000235:genetics
D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse