0377 : Phosphoinositide 3-kinase gamma: a potential clinical target in the prevention of vascular damages inuced by arterial injury

Abstract

Angioplasty with stent placement, used to treat symptomatic atherosclerosis plaques, is frequently complicated by restenosis. This pathology is characteried by fibroproliferative and immuno-inflammatory mechanisms of the arterial wall, called intimal hyperplasia (IH). Our previous results demonstrated that phosphoinositide 3-kinase (??(PI3K(??) was a key mediator of inflammatory processes of the arterial wall leading to atherosclerosis. We now proposed this enzyme as a potential clinical target to prevent vascular damages occuring after arterial lesion leading to IH. As cellular and molecular aspects of IH are still incompletely described, we intended to offer a better understanding ofimmune responses involved in this pathology. Using a mouse model of arterial mechanical injury, we showed that PI3K(?-deficient mice and mice expressing a catalytically-inactive PI3K(?(PI3K(?KD) showed reduced arterial occlusion and accumulation of monocytes and T cells around site of vascular lesion. The transfer of PI3K(?KD CD4 + T cells into Rag2-deficient mice greatly reduced vascular occlusion compared to WT cells, clearly demonstrating the involvement of PI3K(?in CD4 + T cells during IH formation. In addition, we found that IH is associated with increased levels of Th1 and Th17 cytokines. A specific decrease in the Th1 response was observed in the absence of PI3K(?activity, leading to decreased chemokine production by smooth muscle cells. Finally, we show that a short period of treatment with a PI3K(?inhibitor decreased IH development in arterial mechanical injury in mice but also in a rat carotid artery balloon injury model demonstrating the therapeutic potential of this inhibitor. Our work pintpoint PI3K(?as a good target for IH prevention and brings new insights in the immune biology of the disease.