This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Little, P. J. Articles by Wight, T. N. Search for Related Content PubMed PubMed Citation Articles by Little, P. J. Articles by Wight, T. N. Related Collections Lipid and lipoprotein metabolism Other Vascular biology

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:55.)
© 2002 American Heart Association, Inc.

Vascular Biology

Proteoglycans Synthesized by Arterial Smooth Muscle Cells in the Presence of Transforming Growth Factor-ß1 Exhibit Increased Binding to LDLs

Peter J. Little; Lisa Tannock; Katherine L. Olin; Alan Chait; Thomas N. Wight

From the Cell Biology of Diabetes Laboratory (P.J.L.), Baker Medical Research Institute, Melbourne, Victoria, Australia; the Division of Metabolism, Endocrinology and Nutrition (L.T., K.L.O., A.C.), Department of Medicine, and the Department of Pathology (T.N.W.), University of Washington, Seattle; and The Hope Heart Institute (T.N.W.), Seattle, Wash.

Correspondence to Thomas N. Wight, PhD, The Hope Heart Institute, 1124 Columbia Ave, Suite 783, Seattle, WA 98104. E-mail twight{at}hopeheart.org

The "response-to-retention" hypothesis of atherogenesis states that atherogenic lipoproteins, such as low density lipoprotein (LDL), are retained in vessels by proteoglycans and undergo proatherosclerotic modifications. Transforming growth factor (TGF)-ß1 has been identified in atherosclerotic vessels and has been shown to stimulate the synthesis of chondroitin sulfate– and dermatan sulfate–containing proteoglycans by arterial smooth muscle cells (ASMCs), but whether it promotes lipid retention has not been addressed. We investigated whether TGF-ß1 modulates the biosynthesis of proteoglycans by ASMCs in a manner that promotes binding to LDL. Proteoglycans isolated from TGF-ß1–treated ASMCs exhibited enhanced binding to native LDL compared with the binding of proteoglycans isolated from control cultures (K_d 18 µg/mL LDL versus 81 µg/mL LDL, respectively). The increase in proteoglycan-LDL binding caused by TGF-ß1 could be attributed primarily to the glycosaminoglycan portion of the proteoglycans, since the glycosaminoglycan chains liberated from the core proteins of these proteoglycans synthesized in the presence of TGF-ß1 exhibited increased LDL binding as well. Furthermore, glycosaminoglycan chains initiated on xyloside (an initiator of glycosaminoglycan synthesis) in the presence of TGF-ß1 were longer and displayed enhanced binding to LDL compared with the LDL binding of xyloside-initiated glycosaminoglycan chains from control cultures. These results indicate that TGF-ß1 promotes LDL-proteoglycan interaction primarily by its effects on the glycosaminoglycan synthetic machinery of the ASMCs. Therefore, this study supports a proatherogenic role for TGF-ß1.

Key Words: proteoglycans • glycosaminoglycans • smooth muscle cells • transforming growth factor-ß1 • lipoproteins

This article has been cited by other articles:

				P. G. Wilson, J. C. Thompson, N. R. Webb, F. C. de Beer, V. L. King, and L. R. Tannock Serum Amyloid A, but Not C-Reactive Protein, Stimulates Vascular Proteoglycan Synthesis in a Pro-Atherogenic Manner Am. J. Pathol., December 1, 2008; 173(6): 1902 - 1910. [Abstract] [Full Text] [PDF]

				Y. Nakashima, T. N. Wight, and K. Sueishi Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans Cardiovasc Res, July 1, 2008; 79(1): 14 - 23. [Abstract] [Full Text] [PDF]

				H. Dadlani, M. L. Ballinger, N. Osman, R. Getachew, and P. J. Little Smad and p38 MAP Kinase-mediated Signaling of Proteoglycan Synthesis in Vascular Smooth Muscle J. Biol. Chem., March 21, 2008; 283(12): 7844 - 7852. [Abstract] [Full Text] [PDF]

				F. Huang, J. C. Thompson, P. G. Wilson, H. H. Aung, J. C. Rutledge, and L. R. Tannock Angiotensin II increases vascular proteoglycan content preceding and contributing to atherosclerosis development J. Lipid Res., March 1, 2008; 49(3): 521 - 530. [Abstract] [Full Text] [PDF]

				I. Tabas, K. J. Williams, and J. Boren Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis: Update and Therapeutic Implications Circulation, October 16, 2007; 116(16): 1832 - 1844. [Abstract] [Full Text] [PDF]

				K.J. Grande-Allen, N. Osman, M.L. Ballinger, H. Dadlani, S. Marasco, and P.J. Little Glycosaminoglycan synthesis and structure as targets for the prevention of calcific aortic valve disease Cardiovasc Res, October 1, 2007; 76(1): 19 - 28. [Abstract] [Full Text] [PDF]

				Y. Nakashima, H. Fujii, S. Sumiyoshi, T. N. Wight, and K. Sueishi Early Human Atherosclerosis: Accumulation of Lipid and Proteoglycans in Intimal Thickenings Followed by Macrophage Infiltration Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1159 - 1165. [Abstract] [Full Text] [PDF]

				P.-S. Zheng, M. Reis, C. Sparling, D. Y. Lee, D. P. La Pierre, C.-K. A. Wong, Z. Deng, S. Kahai, J. Wen, and B. B. Yang Versican G3 Domain Promotes Blood Coagulation through Suppressing the Activity of Tissue Factor Pathway Inhibitor-1 J. Biol. Chem., March 24, 2006; 281(12): 8175 - 8182. [Abstract] [Full Text] [PDF]

				M. Rodriguez-Lee, G. Ostergren-Lunden, B. Wallin, J. Moses, G. Bondjers, and G. Camejo Fatty Acids Cause Alterations of Human Arterial Smooth Muscle Cell Proteoglycans That Increase the Affinity for Low-Density Lipoprotein Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 130 - 135. [Abstract] [Full Text] [PDF]

				K. Tiedemann, B. Olander, E. Eklund, L. Todorova, M. Bengtsson, M. Maccarana, G. Westergren-Thorsson, and A. Malmstrom Regulation of the chondroitin/dermatan fine structure by transforming growth factor-{beta}1 through effects on polymer-modifying enzymes Glycobiology, December 1, 2005; 15(12): 1277 - 1285. [Abstract] [Full Text] [PDF]

				K. Hashimura, K. Sudhir, J. Nigro, S. Ling, M. R. I. Williams, P. A. Komesaroff, and P. J. Little Androgens Stimulate Human Vascular Smooth Muscle Cell Proteoglycan Biosynthesis and Increase Lipoprotein Binding Endocrinology, April 1, 2005; 146(4): 2085 - 2090. [Abstract] [Full Text] [PDF]

				M. F. Khalil, W. D. Wagner, and I. J. Goldberg Molecular Interactions Leading to Lipoprotein Retention and the Initiation of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2211 - 2218. [Abstract] [Full Text] [PDF]

				T. N. Wight and M. J. Merrilees Proteoglycans in Atherosclerosis and Restenosis: Key Roles for Versican Circ. Res., May 14, 2004; 94(9): 1158 - 1167. [Abstract] [Full Text] [PDF]

				C. D. Meyers, L. R. Tannock, T. N. Wight, and A. Chait Statin-exposed vascular smooth muscle cells secrete proteoglycans with decreased binding affinity for LDL J. Lipid Res., November 1, 2003; 44(11): 2152 - 2160. [Abstract] [Full Text] [PDF]

				A. Schmidt, S. Geigenmueller, W. Voelker, P. Seiler, and E. Buddecke Exogenous nitric oxide causes overexpression of TGF-{beta}1 and overproduction of extracellular matrix in human coronary smooth muscle cells Cardiovasc Res, June 1, 2003; 58(3): 671 - 678. [Abstract] [Full Text] [PDF]

				W. T. Gerthoffer and C. A. Singer Secretory Functions of Smooth Muscle: Cytokines and Growth Factors Mol. Interv., November 1, 2002; 2(7): 447 - 456. [Abstract] [Full Text] [PDF]

				E. Lutgens, M. Gijbels, M. Smook, P. Heeringa, P. Gotwals, V. E. Koteliansky, and M. J.A.P. Daemen Transforming Growth Factor-{beta} Mediates Balance Between Inflammation and Fibrosis During Plaque Progression Arterioscler. Thromb. Vasc. Biol., June 1, 2002; 22(6): 975 - 982. [Abstract] [Full Text] [PDF]