© 2000 American Heart Association, Inc.
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The Insulin-Like Growth Factor Axis
A Review of Atherosclerosis and Restenosis
From the Division of Cardiovascular Diseases (A.B.-G., R.S.S.) and Endocrine Research Unit (C.A.C.), Mayo Clinic and Foundation, Rochester, Minn.
Correspondence to Robert S. Schwartz, MD, Department of Cardiovascular Diseases, Mayo Clinic, 200 First St, SW, Rochester, MN 55905. E-mail schwartzr{at}mayo.edu
Abstract—Insulin-like growth factors I and II (IGF-I and -II) and their regulatory proteins are secreted by cells of the cardiovascular system. They are growth promoters for arterial cells and mediators of cardiovascular disease. IGFs are bound to IGF binding proteins (IGFBPs), which modulate IGF ligand-receptor interaction and consequently to IGF action. IGFBPs are in turn posttranslationally modulated by specific proteases. This dynamic balance (IGFs, IGFBPs, and IGFBP proteases) constitutes the IGF axis and ultimately determines the extent of IGF-dependent cellular effects. Dysregulated actions of this axis influence coronary atherosclerosis through effects on vascular smooth muscle cell growth, migration, and extracellular matrix synthesis in the atherosclerotic plaque. IGF-I promotes macrophage chemotaxis, excess LDL cholesterol uptake, and release of proinflammatory cytokines. Endothelial cells also receive the effects of IGFs stimulating their migration and organization forming capillary networks. Neointimal hyperplasia of restenosis after coronary artery injury is also modulated by the IGF axis. IGFs stimulate vascular smooth muscle cell proliferation and migration to form the neointima and upregulate tropoelastin synthesis after disruption of the elastic layer. Understanding IGF axis regulation establishes a scientific basis for strategies directed to limit or reverse plaque growth and vulnerability in atherosclerosis and in the neointimal hyperplasia of restenosis.
Key Words: insulin-like growth factor • atherosclerosis • restenosis
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T. Kobayashi and K. Kamata Short-term insulin treatment and aortic expressions of IGF-1 receptor and VEGF mRNA in diabetic rats Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1761 - H1768. [Abstract] [Full Text] [PDF]
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E. S. Leinonen, J. T. Salonen, R. M. Salonen, R. A. Koistinen, P. J. Leinonen, S. S. Sarna, and M.-R. Taskinen Reduced IGFBP-1 Is Associated With Thickening of the Carotid Wall in Type 2 Diabetes Diabetes Care, October 1, 2002; 25(10): 1807 - 1812. [Abstract] [Full Text] [PDF]
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B. Askari, M. A. Carroll, M. Capparelli, F. Kramer, R. G. Gerrity, and K. E. Bornfeldt Oleate and Linoleate Enhance the Growth-promoting Effects of Insulin-like Growth Factor-I through a Phospholipase D-dependent Pathway in Arterial Smooth Muscle Cells J. Biol. Chem., September 20, 2002; 277(39): 36338 - 36344. [Abstract] [Full Text] [PDF]
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J. L. Hall, G. H. Gibbons, and J. C. Chatham IGF-I promotes a shift in metabolic flux in vascular smooth muscle cells Am J Physiol Endocrinol Metab, September 1, 2002; 283(3): E465 - E471. [Abstract] [Full Text] [PDF]
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J. Frystyk, T. Ledet, N. Moller, A. Flyvbjerg, and H. Orskov Cardiovascular Disease and Insulin-Like Growth Factor I Circulation, August 20, 2002; 106(8): 893 - 895. [Full Text] [PDF]
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 A. V. Moses, M. A. Jarvis, C. Raggo, Y. C. Bell, R. Ruhl, B. G. M. Luukkonen, D. J. Griffith, C. L. Wait, B. J. Druker, M. C. Heinrich, et al. Kaposi's Sarcoma-Associated Herpesvirus-Induced Upregulation of the c-kit Proto-Oncogene, as Identified by Gene Expression Profiling, Is Essential for the Transformation of Endothelial Cells J. Virol., August 15, 2002; 76(16): 8383 - 8399. [Abstract] [Full Text] [PDF]
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W. Che, N. Lerner-Marmarosh, Q. Huang, M. Osawa, S. Ohta, M. Yoshizumi, M. Glassman, J.-D. Lee, C. Yan, B. C. Berk, et al. Insulin-Like Growth Factor-1 Enhances Inflammatory Responses in Endothelial Cells: Role of Gab1 and MEKK3 in TNF-{alpha}-Induced c-Jun and NF-{kappa}B Activation and Adhesion Molecule Expression Circ. Res., June 14, 2002; 90(11): 1222 - 1230. [Abstract] [Full Text] [PDF]
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M. Zhang, E. P. Smith, H. Kuroda, W. Banach, S. D. Chernausek, and J. A. Fagin Targeted Expression of a Protease-resistant IGFBP-4 Mutant in Smooth Muscle of Transgenic Mice Results in IGFBP-4 Stabilization and Smooth Muscle Hypotrophy J. Biol. Chem., June 7, 2002; 277(24): 21285 - 21290. [Abstract] [Full Text] [PDF]
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Y. G. Amaar, G. R. Thompson, T. A. Linkhart, S.-T. Chen, D. J. Baylink, and S. Mohan Insulin-like Growth Factor-binding Protein 5 (IGFBP-5) Interacts with a Four and a Half LIM Protein 2 (FHL2) J. Biol. Chem., March 29, 2002; 277(14): 12053 - 12060. [Abstract] [Full Text] [PDF]
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 A. K. Berfield and C. K. Abrass IGF-1 Induces Foam Cell Formation in Rat Glomerular Mesangial Cells J. Histochem. Cytochem., March 1, 2002; 50(3): 395 - 403. [Abstract] [Full Text] [PDF]
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S. Zaina, L. Pettersson, B. Ahren, L. Branen, A. B. Hassan, M. Lindholm, R. Mattsson, J. Thyberg, and J. Nilsson Insulin-like Growth Factor II Plays a Central Role in Atherosclerosis in a Mouse Model J. Biol. Chem., February 1, 2002; 277(6): 4505 - 4511. [Abstract] [Full Text] [PDF]
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W. R. P. Agema, J. W. Jukema, S. N. Pimstone, and J. J. P. Kastelein Genetic aspects of restenosis after percutaneous coronary interventions;towards more tailored therapy Eur. Heart J., November 2, 2001; 22(22): 2058 - 2074. [PDF]
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B. Gonzalez, S. Lamas, and E. M. Melian Cooperation between Low Density Lipoproteins and IGF-I in the Promotion of Mitogenesis in Vascular Smooth Muscle Cells Endocrinology, November 1, 2001; 142(11): 4852 - 4860. [Abstract] [Full Text] [PDF]
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 A. Bayes-Genis, C. A. Conover, M. T. Overgaard, K. R. Bailey, M. Christiansen, D. R. Holmes Jr., R. Virmani, C. Oxvig, and R. S. Schwartz Pregnancy-Associated Plasma Protein A as a Marker of Acute Coronary Syndromes N. Engl. J. Med., October 4, 2001; 345(14): 1022 - 1029. [Abstract] [Full Text] [PDF]
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E. P. Smith, A. Kamyar, W. Niu, J. Wang, B. Cercek, S. D. Chernausek, and J. A. Fagin IGF-Binding Protein-4 Expression and IGF-Binding Protein-4 Protease Activity Are Regulated Coordinately in Smooth Muscle During Postnatal Development and After Vascular Injury Endocrinology, October 1, 2001; 142(10): 4420 - 4427. [Abstract] [Full Text] [PDF]
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A. Bayes-Genis, R. S. Schwartz, D. A. Lewis, M. T. Overgaard, M. Christiansen, C. Oxvig, K. Ashai, D. R. Holmes Jr, and C. A. Conover Insulin-Like Growth Factor Binding Protein-4 Protease Produced by Smooth Muscle Cells Increases in the Coronary Artery After Angioplasty Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 335 - 341. [Abstract] [Full Text] [PDF]
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 N. Vaessen, P. Heutink, J. A. Janssen, J. C. M. Witteman, L. Testers, A. Hofman, S. W. J. Lamberts, B. A. Oostra, H. A. P. Pols, and C. M. van Duijn A Polymorphism in the Gene for IGF-I: Functional Properties and Risk for Type 2 Diabetes and Myocardial Infarction Diabetes, March 1, 2001; 50(3): 637 - 642. [Abstract] [Full Text]
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L. Dow and S. Ebrahim Commentary: Lung function and risk of fatal and non-fatal stroke--The Copenhagen City Heart Study Int. J. Epidemiol., February 1, 2001; 30(1): 152 - 153. [Full Text] [PDF]
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 C. Muller, A. Reddert, S. Wassmann, K. Strehlow, M. Bohm, and G. Nickenig Insulin-like growth factor induces up-regulation of AT1-receptor gene expression in vascular smooth muscle cells Journal of Renin-Angiotensin-Aldosterone System, September 1, 2000; 1(3): 273 - 277. [Abstract] [PDF]
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M. J. Kluk and T. Hla Role of the Sphingosine 1-Phosphate Receptor EDG-1 in Vascular Smooth Muscle Cell Proliferation and Migration Circ. Res., September 14, 2001; 89(6): 496 - 502. [Abstract] [Full Text] [PDF]
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H. Chen, D. Li, T. Saldeen, and J. L. Mehta Transforming Growth Factor-{beta}1 Modulates Oxidatively Modified LDL-Induced Expression of Adhesion Molecules: Role of LOX-1 Circ. Res., December 7, 2001; 89(12): 1155 - 1160. [Abstract] [Full Text] [PDF]
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