Abstract
Interleukin‐1β (IL‐1β) is a proinflammatory cytokine increased in the heart following myocardial infarction. Vascular endothelial growth factors (VEGFs) are implicated in angiogenesis due to their involvement in the recruitment and proliferation of endothelial cells. Here we studied expression of VEGFs in response to IL‐1β in rat cardiac microvascular endothelial cells (CMECs) and investigated the signaling pathways involved in the regulation of VEGF‐D. cDNA array analysis indicated that IL‐1β modulates the expression of numerous angiogenesis‐related genes, notably decreasing the expression of VEGF‐D. RT‐PCR and Western blot analyses confirmed decreased expression of VEGF‐D in response to IL‐1β. IL‐1β decreased the expression of VEGF‐C to a lesser extent with no effects on VEGF‐A or ‐B. Inhibition of ERK1/2, JNKs, or PKCα/β~1~ alone partially inhibited IL‐1β‐induced VEGF‐D downregulation. Concurrent inhibition of ERK1/2 or JNKs and PKCα/β~1~ resulted in a synergistic inhibition of IL‐1β‐induced decreases in VEGF‐D. Inhibition of ERK1/2 partially inhibited IL‐1β‐stimulated inactivation of GSK‐3β with no effect on β‐catenin levels. Inhibition of GSK‐3β using SB216763 inhibited basal VEGF‐D expression. We conclude that IL‐1β downregulates VEGF‐D expression in CMECs via the involvement of ERK1/2, JNKs, and PKCα/β~1~. This is the first report to indicate inhibition of VEGF‐D gene expression in response to IL‐1β in cardiac microvascular endothelial cells, a cell type of central interest in angiogenesis. J. Cell. Physiol. 215: 337–343, 2008. © 2007 Wiley‐Liss, Inc.