doi: 10.1161/hq0102.101100
© 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
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 (Kd 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
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