(Circulation. 1997;95:831-839.)
© 1997 American Heart Association, Inc.
Articles |
Human Connective Tissue Growth Factor Is Expressed in Advanced Atherosclerotic Lesions
the Division of Cardiology and Cardiovascular Research Laboratory (B.S.O., A.W., T.F.L.), Department of Cardiovascular Surgery (D.-D.D.), Department of Neurosurgery (N.G.), University Hospital Bern, Bern, Switzerland; Laboratoire de Genetique Moleculaire des Eucaryotes du CNRS (J.-M.G.), Unite 184, INSERM, Strasbourg, France; Department of Medicine (M.N., W.M.), Division of Clinical Chemistry, University Hospital Freiburg, Germany; F. Hoffmann La Roche Ltd (J.R., M.P.), Basel, Switzerland.
Correspondence to Thomas F. Luscher, MD, FACC, Cardiology, University Hospital, CH-8031 Zurich, Switzerland. E-mail OEMAR@UBACLU.UNIBAS.CH.
Background Atherosclerosis affects certain but not all vascular beds of the human circulation. Its molecular mechanisms are only partially understood. Human connective tissue growth factor (hCTGF) is a novel cysteine-rich, secreted polypeptide. hCTGF is implicated in connective tissue formation, which may play an important role in atherosclerosis.
Methods and Results By using a differential cloning technique, we isolated a cDNA clone from a human aorta cDNA library, which is identical to hCTGF. Northern analysis shows that hCTGF mRNA was expressed at 50- to 100-fold higher levels in atherosclerotic blood vessels compared with normal arteries. In vascular smooth muscle cells, high-level expression of hCTGF mRNA was induced by transforming growth factor-ß1. Using in situ hybridization and immunohistochemistry, we found that all advanced atherosclerotic lesions of human carotid arteries (eight patients; mean age, 69; age range, 57 to 85 years) and femoral arteries (two patients; mean age, 71.5 years) that we tested expressed high levels of both hCTGF mRNA and protein. hCTGF expression was localized mainly to smooth muscle cells in the plaque lesions that are negative for proliferating cell nuclear antigen staining. In addition, some CD-31–positive endothelial cells of plaque vessels expressed high levels of hCTGF mRNA and protein. hCTGF-positive cells were found predominantly in areas with extracellular matrix accumulation and fibrosis. In contrast, in normal arteries, we were unable to detect either hCTGF mRNA or immunoreactive hCTGF protein.
Conclusions In the present study, we have shown for the first time that both hCTGF mRNA and protein are expressed in human arteries in vivo and that hCTGF may represent a novel factor expressed at high levels specifically in advanced lesions and may play a role in the development and progression of atherosclerosis.
Key Words: arteriosclerosis • carotid arteries • endothelium • growth substances • stenosis
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 D. K. Ball,, G. A. Surveyor,, J. R. Diehl,, C. L. Steffen,, M. Uzumcu,, M. A. Mirando,, and D. R. Brigstock Characterization of 16- to 20-Kilodalton (kDa) Connective Tissue Growth Factors (CTGFs) and Demonstration of Proteolytic Activity for 38-kDa CTGF in Pig Uterine Luminal Flushings Biol Reprod, October 1, 1998; 59(4): 828 - 835. [Abstract] [Full Text]
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J. Dammeier, H.-D. Beer, M. Brauchle, and S. Werner Dexamethasone Is a Novel Potent Inducer of Connective Tissue Growth Factor Expression. IMPLICATIONS FOR GLUCOCORTICOID THERAPY J. Biol. Chem., July 17, 1998; 273(29): 18185 - 18190. [Abstract] [Full Text] [PDF]
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J. Lin, B. Liliensiek, M. Kanitz, U. Schimanski, H. Bohrer, R. Waldherr, E. Martin, G. Kauffmann, R. Ziegler, and P. P. Nawroth Molecular cloning of genes differentially regulated by TNF-{alpha} in bovine aortic endothelial cells, fibroblasts and smooth muscle cells Cardiovasc Res, June 1, 1998; 38(3): 802 - 813. [Abstract] [Full Text] [PDF]
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B. S. Oemar and T. F. Luscher Connective Tissue Growth Factor : Friend or Foe? Arterioscler Thromb Vasc Biol, August 1, 1997; 17(8): 1483 - 1489. [Abstract] [Full Text]
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A. Hahn, J. Heusinger-Ribeiro, T. Lanz, S. Zenkel, and M. Goppelt-Struebe Induction of Connective Tissue Growth Factor by Activation of Heptahelical Receptors. MODULATION BY Rho PROTEINS AND THE ACTIN CYTOSKELETON J. Biol. Chem., November 22, 2000; 275(48): 37429 - 37435. [Abstract] [Full Text] [PDF]
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R. C. Chambers, P. Leoni, O. P. Blanc-Brude, D. E. Wembridge, and G. J. Laurent Thrombin Is a Potent Inducer of Connective Tissue Growth Factor Production via Proteolytic Activation of Protease-activated Receptor-1 J. Biol. Chem., November 3, 2000; 275(45): 35584 - 35591. [Abstract] [Full Text] [PDF]
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K. Suzuma, K. Naruse, I. Suzuma, N. Takahara, K. Ueki, L. P. Aiello, and G. L. King Vascular Endothelial Growth Factor Induces Expression of Connective Tissue Growth Factor via KDR, Flt1, and Phosphatidylinositol 3-Kinase-Akt-dependent Pathways in Retinal Vascular Cells J. Biol. Chem., December 22, 2000; 275(52): 40725 - 40731. [Abstract] [Full Text] [PDF]
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K. Hishikawa, B. S. Oemar, and T. Nakaki Static Pressure Regulates Connective Tissue Growth Factor Expression in Human Mesangial Cells J. Biol. Chem., May 11, 2001; 276(20): 16797 - 16803. [Abstract] [Full Text] [PDF]
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P. R. Segarini, J. E. Nesbitt, D. Li, L. G. Hays, J. R. Yates III, and D. F. Carmichael The Low Density Lipoprotein Receptor-related Protein/alpha 2-Macroglobulin Receptor Is a Receptor for Connective Tissue Growth Factor J. Biol. Chem., October 26, 2001; 276(44): 40659 - 40667. [Abstract] [Full Text] [PDF]
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