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Article Dans Une Revue Journal of Cell Science Année : 2020

A non-catalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage

Adrien Lupieri
  • Fonction : Auteur
Régis Blaise
  • Fonction : Auteur
Alessandra Ghigo
  • Fonction : Auteur
Natalia Smirnova
  • Fonction : Auteur
Marie-Kerguelen Sarthou
  • Fonction : Auteur
Nicole Malet
  • Fonction : Auteur
Isabelle Limon
  • Fonction : Auteur
Pierre Vincent
Emilio Hirsch
  • Fonction : Auteur
Stéphanie Gayral
  • Fonction : Auteur
Muriel Laffargue

Résumé

Arterial remodeling in hypertension and intimal hyperplasia involves inflammation and disrupted flow, both of which contribute to smooth muscle cell dedifferentiation and proliferation. In this context, our previous results identified phosphoinositide 3-kinase γ (PI3Kγ) as an essential factor in inflammatory processes of the arterial wall. Here, we identify for the first time a kinase-independent role of nonhematopoietic PI3Kγ in the vascular wall during intimal hyperplasia using PI3Kγ-deleted mice and mice expressing a kinase-dead version of the enzyme. Moreover, we found that the absence of PI3Kγ in vascular smooth muscle cells (VSMCs) leads to modulation of cell proliferation, associated with an increase in intracellular cAMP levels. Real-time analysis of cAMP dynamics revealed that PI3Kγ modulates the degradation of cAMP in primary VSMCs independently of its kinase activity through regulation of the enzyme phosphodiesterase 4. Importantly, the use of an N-terminal competing peptide of PI3Kγ blocked primary VSMC proliferation. These data provide evidence for a kinase-independent role of PI3Kγ in arterial remodeling and reveal novel strategies targeting the docking function of PI3Kγ for the treatment of cardiovascular diseases.
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Dates et versions

hal-02999224 , version 1 (15-11-2020)

Identifiants

Citer

Adrien Lupieri, Régis Blaise, Alessandra Ghigo, Natalia Smirnova, Marie-Kerguelen Sarthou, et al.. A non-catalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage. Journal of Cell Science, 2020, 133 (13), pp.jcs245969. ⟨10.1242/jcs.245969⟩. ⟨hal-02999224⟩
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