Myocyte-dependent regulation of endothelial cell syndecan-4 expression. Role of TNF-alpha.
Syndecan-4 is a unique member of the syndecan gene family that has the ability to bind and activate protein kinase C-alpha. Whereas increased syndecan-4 levels have been noted in ischemic hearts, little is known regarding the regulation of its expression. To investigate the role of cardiac myocytes in induction of syndecan-4 expression, human endothelial cells (ECV304) were exposed to a medium conditioned by primary mouse cardiac myocytes or H9c2 cells. The medium conditioned by hypoxic but not normal myocytes was able to induce syndecan-4 expression in ECV cells. Western analysis of the conditioned medium demonstrated an increased presence of tumor necrosis factor-alpha (TNF-alpha) in the medium conditioned by hypoxic but not normal myoblasts. Primary cardiac myocytes collected from the wild type C57/129 but not the homozygous TNF-alpha-/- knockout mice were able to induce syndecan-4 expression in ECV cells when cultured under hypoxic conditions. In vitro studies demonstrated that TNF-alpha induced endothelial cell syndecan-4 expression by both increasing syndecan-4 gene expression in an NF-kappaB-dependent manner and by prolonging syndecan-4 mRNA half-life. We conclude that TNF-alpha is the principal factor produced by the ischemic myocytes that is responsible for induction of endothelial cell syndecan-4 expression and that this requires both transcriptional and posttranscriptional mechanisms.
D000818:Animals; D015687:Cell Hypoxia; D017077:Culture Media, Conditioned; D004727:Endothelium / Q000502:physiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009206:Myocardium / Q000166:cytology*; D011509:Proteoglycans / Q000096:biosynthesis* / Q000235:genetics; D053671:Syndecan-4; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology