Neuregulin-1alpha and beta 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 alpha and beta variants. Comparison of the activity of recombinant NRG1alpha and NRG1beta EGF-like domain proteins in cardiac myocytes shows that the beta ligand is a more potent activator of receptor phosphorylation and intracellular signaling than the alpha ligand, and only the beta ligand stimulated glucose uptake and protein synthesis in these culture conditions. Thus, cardiac microvascular endothelial cells express multiple NRG1 isotypes, but only beta-variants are biologically active on cardiac myocytes.
Cote
Gregory M
GM
Whitaker Cardiovascular Institute and Molecular Stress Response Unit, Cardiovascular Division, Department of Medicine, Boston University Medical Center, 650 Albany Street, Boston, X-320, MA 02118, USA.
Miller
Thomas A
TA
Lebrasseur
Nathan K
NK
Kuramochi
Yukio
Y
Sawyer
Douglas B
DB
D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D066246:ErbB Receptors; D005947:Glucose; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins; C490580:Nrg1 protein, rat; C117467:neuregulin beta; C587691:Erbb4 protein, rat