Distribution of chimeric IGF binding protein (IGFBP)-3 and IGFBP-4 in the rat heart: Importance of C-terminal basic region

IGF binding proteins-3 and -4, whether given in the perfused rat heart or g iven iv in the intact animal, cross the microvascular endothelium of the he art and distribute in subendothelial tissues. IGF binding protein-3, like I GF-I/II, localizes in cardiac muscle, with lesser concentrations in CT elem ents. In contrast, IGFBP-4 preferentially localizes in CT. In this study, c himeric 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 prot ein-3(4) and IGF binding protein-4(3). Perfused IGF binding protein-3(4) be haved like IGF binding protein-4, localizing in connective tissue elements, whereas IGF binding protein-4(3) now localized in cardiac muscle at concen trations identical to perfused IGF binding protein-3. To determine whether these small mutations altered the affinity of the chimera for cells, the ab ility of (125)-IGF binding protein-3(4) and I-125-IGF binding protein-4(3) to bind to microvascular endothelial cells was determined and compared with IGF binding protein-3(4) IGF binding protein-3(4) retained 15% of the bind ing capacity of IGF binding protein-3, whereas IGF binding protein-4(3) bou nd 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 correspondi ng region of IGF binding protein-4 can alter their affinity for cultured ce lls and influence their tissue distribution in the rat heart.