Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase-γ Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes

Medientyp: E-Artikel
Titel: Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase-γ Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes
Beteiligte: Fougerat, Anne; Gayral, Stéphanie; Gourdy, Pierre; Schambourg, Alexia; Rückle, Thomas; Schwarz, Matthias K.; Rommel, Christian; Hirsch, Emilio; Arnal, Jean-François; Salles, Jean-Pierre; Perret, Bertrand; Breton-Douillon, Monique; Wymann, Matthias P.; Laffargue, Muriel
Erschienen: Ovid Technologies (Wolters Kluwer Health), 2008
Erschienen in: Circulation
Sprache: Englisch
DOI: 10.1161/circulationaha.107.720466
ISSN: 0009-7322; 1524-4539
Schlagwörter: Physiology (medical) ; Cardiology and Cardiovascular Medicine
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Beschreibung: <jats:p> <jats:bold> <jats:italic>Background—</jats:italic> </jats:bold> The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase-γ (PI3Kγ) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3Kγ in the cardiovascular system suggest that PI3Kγ plays a role in atherosclerosis. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> Here, we demonstrate that a specific PI3Kγ inhibitor (AS605240) is effective in murine models of established atherosclerosis. Intraperitoneal administration of AS605240 (10 mg/kg daily) significantly decreased early atherosclerotic lesions in apolipoprotein E–deficient mice and attenuated advanced atherosclerosis in low-density lipoprotein receptor–deficient mice. Furthermore, PI3Kγ levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor–deficient mice transplanted with wild-type or PI3Kγ-deficient bone marrow demonstrated that functional PI3Kγ in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3Kγ activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> These data identify PI3Kγ as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation, such as fatty streak constitution, cellular composition, and final fibrous cap establishment. </jats:p>
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