The Journal of Experimental Medicine
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Published online 11 April 2005 doi:10.1084/jem.20040995
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 8, 1217-1228
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ARTICLE

 Protection from angiotensin II–mediated vasculotoxic and hypertensive response in mice lacking PI3K{gamma}

Carmine Vecchione1, Enrico Patrucco2, Gennaro Marino1, Laura Barberis2, Roberta Poulet1, Alessandra Aretini1, Angelo Maffei1, Maria Teresa Gentile1, Marianna Storto1, Ornella Azzolino2, Mara Brancaccio2, Gian Luca Colussi1, Umberto Bettarini1, Fiorella Altruda2, Lorenzo Silengo2, Guido Tarone2, Mathias P. Wymann3, Emilio Hirsch2, and Giuseppe Lembo1,4

1 Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, Italy
2 Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, 10126 Torino, Italy
3 Department of Clinical and Biological Sciences, Institute of Biochemistry and Genetics, University of Basel, CH-4058 Basel, Switzerland
4 Dipartimento di Medicina Sperimentale e Patologia, Università La Sapienza di Roma, 00161 Roma, Italy

CORRESPONDENCE Emilio Hirsch: Emilio.Hirsch{at}unito.it OR Giuseppe Lembo: lembo{at}neuromed.it

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. PI3K{gamma} was found to play a role in angiotensin II–evoked smooth muscle contraction in two crucial, distinct signaling pathways. In response to angiotensin II, PI3K{gamma} was required for the activation of Rac and the subsequent triggering of ROS production. Conversely, PI3K{gamma} was necessary to activate protein kinase B/Akt, which, in turn, enhanced L-type Ca2+ channel–mediated extracellular Ca2+ entry. These data indicate that PI3K{gamma} is a key transducer of the intracellular signals that are evoked by angiotensin II and suggest that blocking PI3K{gamma} function might be exploited to improve therapeutic intervention on hypertension.

Abbreviations used: ANOVA, analysis of variance; DN-Akt, dominant-negative PB/Akt mutant; EGFR, epidermal growth factor receptor; ERK, extracellular signal–regulated kinase; GPCR, G protein–coupled receptor; GSK, glycogen synthase kinase; MCSA, media cross- sectional area; NAD(P)H, nicotinamide adenine dinucleotide (phosphate); PI3K, phosphoinositide 3-kinase; PtdIns, phosphoinositides; PKB, protein kinase B; PTX, pertussis toxin; ROS, reactive oxygen species.

E. Hirsch and G. Lembo contributed equally to this work.


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