PI3Kγ inhibition reduces blood pressure by a vasorelaxant Akt/L-type calcium channel mechanism.
OBJECTIVE
The lipid and protein kinase phosphoinositide 3-kinase γ (PI3Kγ) is abundantly expressed in inflammatory cells and in the cardiovascular tissue. In recent years, its role in inflammation and in cardiac function and remodelling has been unravelled, highlighting the beneficial effects of its pharmacological inhibition. Furthermore, a role for PI3Kγ in the regulation of vascular tone has been emphasized. However, the impact of this signalling in the control of blood pressure is still poorly understood. Our study investigated the effect of a selective inhibition of PI3Kγ, obtained by using two independent small molecules, on blood pressure. Moreover, we dissected the molecular mechanisms involved in control of contraction of resistance arteries by PI3Kγ.


RESULTS
We showed that inhibition of PI3Kγ reduced blood pressure in normotensive and hypertensive mice in a concentration-dependent fashion. This effect was dependent on enhanced vasodilatation, documented in vivo by decreased peripheral vascular resistance, and ex vivo by vasorelaxing effects on isolated resistance vessels. The vasorelaxation induced by PI3Kγ inhibition relied on blunted pressure-induced Akt phosphorylation and a myogenic contractile response. Molecular insights revealed that PI3Kγ inhibition affected smooth muscle L-type calcium channel current density and calcium influx by impairing plasma membrane translocation of the α1C L-type calcium channel subunit responsible for channel open-state probability.


CONCLUSIONS
Overall our findings suggest that PI3Kγ inhibition could be a novel tool to modulate calcium influx in vascular smooth muscle cells, thus relaxing resistance arteries and lowering blood pressure.
Department of Angiocardioneurology, IRCCS Neuromed, Pozzilli, Isernia, Italy.
Daniela
D
Carnevale
Carmine
C
Vecchione
Giada
G
Mascio
Giovanni
G
Esposito
Giuseppe
G
Cifelli
Katiuscia
K
Martinello
Alessandro
A
Landolfi
Giulio
G
Selvetella
Paolo
P
Grieco
Antonio
A
Damato
Elio
E
Franco
Hannelore
H
Haase
Angelo
A
Maffei
Elisa
E
Ciraolo
Sergio
S
Fucile
Giacomo
G
Frati
Orazio
O
Mazzoni
Emilio
E
Hirsch
Giuseppe
G
Lembo
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011810:Quinoxalines / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D051057:Proto-Oncogene Proteins c-akt