Interferon-γ Induces Human Vascular Smooth Muscle Cell Proliferation and Intimal Expansion by Phosphatidylinositol 3-Kinase–Dependent Mammalian Target of Rapamycin Raptor Complex 1 Activation

• DOI: 10.1161/circresaha.107.151068
• Publication Date: 2007-07-27T01:36:37Z
• Authors: Yinong Wang; Yalai Bai; Lingfeng Qin; Pei Zhang; Tai Yi; Stephanie A. Tees...; Liping Zhao; Jordan S. Pober; George Tellides
• Keywords: Graft Rejection; Hyperplasia; Genetic Vectors; Gene Transfer Techniques; Coronary Artery Disease; Mice, SCID; Mechanistic Target of Rapamycin Complex 1; Coronary Vessels; Adenoviridae; 3. Good health; Interferon-gamma; Mice; 03 medical and health sciences; 0302 clinical medicine; Chromones; Animals; Humans; Enzyme Inhibitors; Aorta; Cells, Cultured; Immunosuppressive Agents; Adaptor Proteins, Signal Transducing; Cell Proliferation

Interferon (IFN)-γ, a cytokine characteristically expressed in arteriosclerotic diseases, acts directly on vascular smooth muscle cells to induce cellular proliferation and intimal expansion. Signaling by the mammalian target of rapamycin raptor complex, known as mTORC1, is associated with cell growth active within lesions but not be triggered proinflammatory factors cells. We investigated mechanisms for proarteriosclerotic effects IFN-γ absence leukocytes exploiting species specificity this chimeric model immunodeficient mouse recipients bearing human coronary artery grafts intravenously inoculated adenovirus encoding transgene. found that IFN-γ–mediated expansion were phosphorylation mTORC1 effector ribosomal protein S6 kinase 1, graft morphological changes 1 activation inhibited inhibitor vivo, IFN-γ–induced signaling was dependent phosphatidylinositol 3-kinase activity under serum-free conditions vitro. Our work establishes an immunologic stimulus cells, emphasizes critical immune-mediated remodeling, provides further mechanistic insight into successful clinical application therapy atherosclerosis arteriosclerosis.