title: Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma.
abstract: 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.
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vecchione
authors.forename: Enrico
authors.initials: E
authors.lastname: Patrucco
authors.forename: Gennaro
authors.initials: G
authors.lastname: Marino
authors.forename: Laura
authors.initials: L
authors.lastname: Barberis
authors.forename: Roberta
authors.initials: R
authors.lastname: Poulet
authors.forename: Alessandra
authors.initials: A
authors.lastname: Aretini
authors.forename: Angelo
authors.initials: A
authors.lastname: Maffei
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Gentile
authors.forename: Marianna
authors.initials: M
authors.lastname: Storto
authors.forename: Ornella
authors.initials: O
authors.lastname: Azzolino
authors.forename: Mara
authors.initials: M
authors.lastname: Brancaccio
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Colussi
authors.forename: Umberto
authors.initials: U
authors.lastname: Bettarini
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.forename: Guido
authors.initials: G
authors.lastname: Tarone
authors.forename: Mathias P
authors.initials: MP
authors.lastname: Wymann
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
mesh_terms: 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*
chemical_list: D000804:Angiotensin II; D002118:Calcium; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents