Abstract
Interferon (IFN)-gamma, 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 and is active within arteriosclerotic lesions but is not known to be triggered by proinflammatory factors in vascular smooth muscle cells. We investigated the mechanisms for the proarteriosclerotic effects of IFN-gamma in the absence of leukocytes by exploiting the species specificity of this cytokine in a chimeric model of immunodeficient mouse recipients bearing human coronary artery grafts and intravenously inoculated with adenovirus encoding a human IFN-gamma transgene. We found that IFN-gamma-mediated vascular smooth muscle cell proliferation and intimal expansion were associated with phosphorylation of the mTORC1 effector ribosomal protein S6 kinase 1, that the graft morphological changes and S6 kinase 1 activation were inhibited by the mTORC1 inhibitor rapamycin in vivo, and that IFN-gamma-induced mTORC1 signaling was dependent on phosphatidylinositol 3-kinase activity under serum-free conditions in vitro. Our work establishes an immunologic stimulus for mTORC1 signaling in vascular smooth muscle cells, emphasizes that mTORC1 activation is critical in immune-mediated vascular remodeling, and provides further mechanistic insight into the successful clinical application of rapamycin therapy for atherosclerosis and graft arteriosclerosis.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adenoviridae / genetics
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Animals
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Aorta / enzymology
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Aorta / metabolism
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Cell Proliferation* / drug effects
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Cells, Cultured
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Chromones / pharmacology
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Coronary Artery Disease / enzymology
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Coronary Artery Disease / metabolism*
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Coronary Artery Disease / pathology
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Coronary Vessels / enzymology
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Coronary Vessels / metabolism
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Coronary Vessels / transplantation
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Enzyme Inhibitors / pharmacology
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Gene Transfer Techniques
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Genetic Vectors
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Graft Rejection / enzymology
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Graft Rejection / metabolism
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Humans
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Hyperplasia
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Immunosuppressive Agents / pharmacology
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Interferon-gamma / genetics
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Interferon-gamma / metabolism*
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, SCID
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Morpholines / pharmacology
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Multiprotein Complexes
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / enzymology
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Muscle, Smooth, Vascular / metabolism*
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Muscle, Smooth, Vascular / pathology
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Muscle, Smooth, Vascular / transplantation
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Myocytes, Smooth Muscle / enzymology
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Myocytes, Smooth Muscle / metabolism
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Proteins / metabolism*
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Regulatory-Associated Protein of mTOR
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Time Factors
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Tissue Culture Techniques
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism*
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Transplantation, Heterologous
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Tunica Intima / drug effects
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Tunica Intima / enzymology
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Tunica Intima / metabolism*
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Tunica Intima / pathology
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Tunica Intima / transplantation
Substances
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Adaptor Proteins, Signal Transducing
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Chromones
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Enzyme Inhibitors
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Immunosuppressive Agents
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Morpholines
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Multiprotein Complexes
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Phosphoinositide-3 Kinase Inhibitors
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Proteins
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RPTOR protein, human
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Regulatory-Associated Protein of mTOR
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Transcription Factors
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Interferon-gamma
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Mechanistic Target of Rapamycin Complex 1
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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ribosomal protein S6 kinase, 70kD, polypeptide 1
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Sirolimus