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Distribution of Chimeric IGF Binding Protein (IGFBP)-3 and IGFBP-4 in the Rat Heart: Importance of C-Terminal Basic Region

Department of Internal Medicine, Diabetes and Endocrinology Research Center, Veterans Administration Medical Center, The University of Iowa, Iowa City, Iowa 52246

Address all correspondence and requests for reprints to: Robert S. Bar, M.D., The University of Iowa, Department of Internal Medicine, ENDO-3E19 Veterans Administration Medical Center, Iowa City, Iowa 52246. E-mail: rbar{at}icva.gov

IGF binding proteins-3 and -4, whether given in the perfused rat heart or given iv in the intact animal, cross the microvascular endothelium of the heart and distribute in subendothelial tissues. IGF binding protein-3, like IGF-I/II, localizes in cardiac muscle, with lesser concentrations in CT elements. In contrast, IGFBP-4 preferentially localizes in CT. In this study, chimeric IGF binding proteins were prepared in which a basic 20-amino-acid C-terminal region of IGF binding protein-3 was switched with the homologous region of IGF binding protein-4, and vice-versa, to create IGF binding protein-3₄ and IGF binding protein-4₃. Perfused IGF binding protein-3₄ behaved like IGF binding protein-4, localizing in connective tissue elements, whereas IGF binding protein-4₃ now localized in cardiac muscle at concentrations identical to perfused IGF binding protein-3. To determine whether these small mutations altered the affinity of the chimera for cells, the ability of ¹²⁵I-IGF binding protein-3₄ and ¹²⁵I-IGF binding protein-4₃ to bind to microvascular endothelial cells was determined and compared with IGF binding protein-3. IGF binding protein-3₄ retained 15% of the binding capacity of IGF binding protein-3, whereas IGF binding protein-4₃ bound to microvessel endothelial cells with higher affinity and greater total binding than that of IGF binding protein-3. We conclude that small changes in the C-terminal basic domain of IGF binding protein-3 and the corresponding region of IGF binding protein-4 can alter their affinity for cultured cells and influence their tissue distribution in the rat heart.