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PMID: 15824082 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma.

The Journal of experimental medicine ·Vol. 201 ·No. 8 ·2005-04-18 ·Pages 1217-28

Vecchione C, Patrucco E, Marino G, Barberis L, Poulet R, Aretini A, Maffei A, Gentile MT, Storto M, Azzolino O, Brancaccio M, Colussi GL, Bettarini U, Altruda F, Silengo L, Tarone G, Wymann MP, Hirsch E, Lembo G

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.

MeSH Terms
Angiotensin II/pharmacology Animals Aorta Calcium/metabolism Cells, Cultured Hypertension/chemically induced,prevention & control Isoenzymes/antagonists & inhibitors,deficiency Male Mesenteric Arteries Mice Mice, Knockout Muscle, Smooth, Vascular/drug effects,metabolism Phosphatidylinositol 3-Kinases/deficiency Phosphoinositide-3 Kinase Inhibitors Reactive Oxygen Species/metabolism Vasoconstriction Vasoconstrictor Agents/pharmacology
Chemicals
Isoenzymes Phosphoinositide-3 Kinase Inhibitors Reactive Oxygen Species Vasoconstrictor Agents Angiotensin II Calcium
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Vecchione Carmine
Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, Italy.
Patrucco Enrico
Marino Gennaro
Barberis Laura
Poulet Roberta
Aretini Alessandra
Maffei Angelo
Gentile Maria Teresa
Storto Marianna
Azzolino Ornella
Brancaccio Mara
Colussi Gian Luca
Bettarini Umberto
Altruda Fiorella
Silengo Lorenzo
Tarone Guido
Wymann Mathias P
Hirsch Emilio
Lembo Giuseppe
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20040995
Published
2005-04-18
Epub
2005-00-11
Pages
1217-28
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2213159
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20040995 PMC Full Text View journal details
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