Neuregulin-1α and β isoform expression in cardiac microvascular endothelial cells and function in cardiac myocytes in vitro

Neuregulins (NRGs) are a family of alternatively spliced growth factors that act through receptor tyrosine kinases of the epidermal growth factor (EGF) receptor family in diverse tissues. The NRG-erbB signaling axis is a critical mediator of cardiac development, and growing evidence supports a role for this system in the intricate cross-talk between the microvascular endothelium and myocytes in the adult heart. The purpose of this study was first to examine the expression of splice variants of the NRG1 gene in adult rat cardiac microvascular endothelial cells and second to compare the function of these variants in cardiac myocytes. We demonstrate that cardiac microvascular endothelial cells in rat culture express multiple Type I NRG1 gene products, including both α and β variants. Comparison of the activity of recombinant NRG1α and NRG1β EGF-like domain proteins in cardiac myocytes shows that the β ligand is a more potent activator of receptor phosphorylation and intracellular signaling than the α ligand, and only the β ligand stimulated glucose uptake and protein synthesis in these culture conditions. Thus, cardiac microvascular endothelial cells express multiple NRG1 isotypes, but only β-variants are biologically active on cardiac myocytes.