Published online before print November 4, 2004, doi: 10.1161/01.RES.0000149568.85071.FB
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© 2004 American Heart Association, Inc.
Molecular Medicine |
Fibulin-5 Is a Novel Binding Protein for Extracellular Superoxide Dismutase
From the Division of Cardiology (A.D.N., S.I., V.J., M.F., M.U.-F., T.F.), Department of Medicine, Emory University School of Medicine, Atlanta, Ga; and the Department of Molecular Biology (H.Y.), University of Texas Southwestern Medical Center, Dallas.
Correspondence to Tohru Fukai, MD, PhD, Division of Cardiology, Emory University School of Medicine, 1639 Pierce Dr, WMB 319, Atlanta, GA 30322. E-mail tfukai{at}emory.edu
The extracellular superoxide dismutase (ecSOD) plays an important role in atherosclerosis and endothelial function by modulating levels of the superoxide anion (O2·–) in the extracellular space. Although heparan sulfate proteoglycan is an important ligand for ecSOD, little is known about other biological binding partners of ecSOD. The goal of this study was to identify novel proteins that interact with ecSOD. A yeast two-hybrid screening of a human aorta cDNA library using ecSOD as bait identified fibulin-5 as a predominant binding protein for ecSOD. Further analysis showed that the binding domain of ecSOD within fibulin-5 mapped to its C-terminal domain. In vitro pulldown assays and coimmunoprecipitation analysis further confirmed that ecSOD interacts with fibulin-5 in vitro and in vivo. Studies using fibulin-5–/– mice indicated that fibulin-5 is required for binding of ecSOD to vascular tissue. Importantly, the decrease in tissue-bound ecSOD levels in aortas from fibulin-5–/– mice was associated with an increase in vascular O2·– levels. Furthermore, immunohistochemical analysis using ApoE–/– mice suggested a codistribution of ecSOD and fibulin-5 in atherosclerotic vessels. In summary, we provide in this study the first evidence that the ecSOD-fibulin-5 interaction is required for ecSOD binding to vascular tissues, thereby regulating vascular O2·– levels. This interaction may represent a novel mechanism for controlling vascular redox state in the extracellular space in various cardiovascular diseases such as atherosclerosis and hypertension in which oxidative stress is increased.
Key Words: superoxide dismutase • fibulin-5 • extracellular matrix • atherosclerosis • superoxide
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