Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kγ

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.