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PI3kγ inhibition reduces blood pressure by a vasorelaxant Akt/LTCC mechanism

Authors

  • D. Carnevale
  • C. Vecchione
  • G. Mascio
  • G. Esposito
  • G. Cifelli
  • K. Martinello
  • A. Landolfi
  • G. Selvetella
  • P. Grieco
  • A. Damato
  • E. Franco
  • H. Haase
  • A. Maffei
  • E. Ciraolo
  • S. Fucile
  • G. Frati
  • O. Mazzoni
  • E. Hirsch
  • G. Lembo

Journal

  • Cardiovascular Research

Citation

  • Cardiovasc Res 93 (1): 200-209

Abstract

  • Aims: The lipid and protein kinase phosphoinositide 3-kinase {gamma} (PI3K{gamma}) is abundantly expressed in inflammatory cells and in the cardiovascular tissue. In the past years, its role in inflammation and in cardiac function and remodeling has been unraveled, highlighting beneficial effects recruited by its pharmacological inhibition. Furthermore, it has been emphasized a role of PI3K{gamma} in the regulation of vascular tone. However, the impact of this signaling in the control of blood pressure (BP) is still poorly unknown. Our study investigated the effect of a selective inhibition of PI3K{gamma}, obtained by using two independent small molecules, on BP. Moreover, we dissected the molecular mechanisms involved in PI3K{gamma} control of contraction of resistance arteries. Methods and Results: We showed that PI3K{gamma} inhibition reduced BP in normotensive and hypertensive mice, in a concentration-dependent fashion. This effect was dependent on enhanced vasodilation, documented in vivo by decreased peripheral vascular resistances, and ex vivo by vasorelaxing effects on isolated resistance vessels. The vasorelaxation induced by PI3Kγ inhibition relied on blunted pressure-induced Akt phosphorylation and myogenic contractile response. Molecular insights revealed that PI3K{gamma} inhibition affected smooth muscle L-type calcium channel (LTCC) current density and calcium influx, by impairing plasma membrane translocation of {alpha}1C LTCC subunit, responsible for channel open-state probability. Conclusions: Overall our findings prospect that PI3K{gamma} inhibition could be also a novel tool to modulate calcium influx in vascular smooth muscle cells, thus relaxing resistance arteries and lowering BP.


DOI

doi:10.1093/cvr/cvr288