Distinct effects of leukocyte and cardiac phosphoinositide 3-kinase γ activity in pressure overload-induced cardiac failure

Federico Damilano, Irene Franco, Cinzia Perrino, Katrin Schaefer, Ornella Azzolino, Daniela Carnevale, Giuseppe Cifelli, Pierluigi Carullo, Riccardo Ragona, Alessandra Ghigo, Alessia Perino, Giuseppe Lembo, Emilio Hirsch

Research output: Contribution to journalArticle

Abstract

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. Methods and 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.

Original languageEnglish
Pages (from-to)391-399
Number of pages9
JournalCirculation
Volume123
Issue number4
DOIs
Publication statusPublished - Feb 1 2011

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1-Phosphatidylinositol 4-Kinase
Leukocytes
Heart Failure
Pressure
Constriction
Fibrosis
Bone Marrow Cells
Dilatation
Immune System
Bone Marrow
Phosphotransferases
Inflammation

Keywords

  • fibrosis
  • heart failure
  • inflammation
  • PI3Kγ
  • signal transduction

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Distinct effects of leukocyte and cardiac phosphoinositide 3-kinase γ activity in pressure overload-induced cardiac failure. / Damilano, Federico; Franco, Irene; Perrino, Cinzia; Schaefer, Katrin; Azzolino, Ornella; Carnevale, Daniela; Cifelli, Giuseppe; Carullo, Pierluigi; Ragona, Riccardo; Ghigo, Alessandra; Perino, Alessia; Lembo, Giuseppe; Hirsch, Emilio.

In: Circulation, Vol. 123, No. 4, 01.02.2011, p. 391-399.

Research output: Contribution to journalArticle

Damilano, Federico ; Franco, Irene ; Perrino, Cinzia ; Schaefer, Katrin ; Azzolino, Ornella ; Carnevale, Daniela ; Cifelli, Giuseppe ; Carullo, Pierluigi ; Ragona, Riccardo ; Ghigo, Alessandra ; Perino, Alessia ; Lembo, Giuseppe ; Hirsch, Emilio. / Distinct effects of leukocyte and cardiac phosphoinositide 3-kinase γ activity in pressure overload-induced cardiac failure. In: Circulation. 2011 ; Vol. 123, No. 4. pp. 391-399.
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