Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma.
Hypertension affects nearly 20% of the population in Western countries and strongly increases the risk for cardiovascular diseases. In the pathogenesis of hypertension, the vasoactive peptide of the renin-angiotensin system, angiotensin II and its G protein-coupled receptors (GPCRs), play a crucial role by eliciting reactive oxygen species (ROS) and mediating vessel contractility. Here we show that mice lacking the GPCR-activated phosphoinositide 3-kinase (PI3K)gamma are protected from hypertension that is induced by administration of angiotensin II in vivo. PI3Kgamma was found to play a role in angiotensin II-evoked smooth muscle contraction in two crucial, distinct signaling pathways. In response to angiotensin II, PI3Kgamma was required for the activation of Rac and the subsequent triggering of ROS production. Conversely, PI3Kgamma was necessary to activate protein kinase B/Akt, which, in turn, enhanced L-type Ca(2+) channel-mediated extracellular Ca(2+) entry. These data indicate that PI3Kgamma is a key transducer of the intracellular signals that are evoked by angiotensin II and suggest that blocking PI3Kgamma function might be exploited to improve therapeutic intervention on hypertension.
Vecchione
Carmine
C
Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, Italy.
Patrucco
Enrico
E
Marino
Gennaro
G
Barberis
Laura
L
Poulet
Roberta
R
Aretini
Alessandra
A
Maffei
Angelo
A
Gentile
Maria Teresa
MT
Storto
Marianna
M
Azzolino
Ornella
O
Brancaccio
Mara
M
Colussi
Gian Luca
GL
Bettarini
Umberto
U
Altruda
Fiorella
F
Silengo
Lorenzo
L
Tarone
Guido
G
Wymann
Mathias P
MP
Hirsch
Emilio
E
Lembo
Giuseppe
G
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000172:deficiency; D008297:Male; D008638:Mesenteric Arteries; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000804:Angiotensin II; D002118:Calcium; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents