Downregulation of VEGF‐D expression by interleukin‐1β in cardiac microvascular endothelial cells is mediated by MAPKs and PKCα/β₁

Abstract

Interleukin-1beta (IL-1beta) 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-1beta 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-1beta 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-1beta. IL-1beta decreased the expression of VEGF-C to a lesser extent with no effects on VEGF-A or -B. Inhibition of ERK1/2, JNKs, or PKCalpha/beta1 alone partially inhibited IL-1beta-induced VEGF-D downregulation. Concurrent inhibition of ERK1/2 or JNKs and PKCalpha/beta1 resulted in a synergistic inhibition of IL-1beta-induced decreases in VEGF-D. Inhibition of ERK1/2 partially inhibited IL-1beta-stimulated inactivation of GSK-3beta with no effect on beta-catenin levels. Inhibition of GSK-3beta using SB216763 inhibited basal VEGF-D expression. We conclude that IL-1beta downregulates VEGF-D expression in CMECs via the involvement of ERK1/2, JNKs, and PKCalpha/beta(1). This is the first report to indicate inhibition of VEGF-D gene expression in response to IL-1beta in cardiac microvascular endothelial cells, a cell type of central interest in angiogenesis.

RNAi targeting urokinase‐type plasminogen activator receptor inhibits metastasis and progression of oral squamous cell carcinoma in vivo

“…52,53 Mountain et al recently reported that the downregulation of VEGF-D expression by interleukin-1 beta in cardiac microvascular endothelial cells is mediated by MAPKs (ERK1/2 and JNK pathways) and protein kinase C a/b1 (PKC a/b1). 54 Therefore, the mechanism that u-PAR activates the downstream pathways (such as MAPKs pathways) through its interaction with different integrins, provides probably an explanation for the downregulation of mRNA expression of VEGF-C, VEGF-D and VEGFR-3 by RNAi targeting u-PAR in our study. However, this deduction should be confirmed in further studies.…”

Histone Deacetylase-1 Is Enriched at the Platelet-derived Growth Factor-D Promoter in Response to Interleukin-1β and Forms a Cytokine-inducible Gene-silencing Complex with NF-κB p65 and Interferon Regulatory Factor-1

“…Angiotensin II and transforming growth factor-␤ (TGF-␤) negatively regulate hepatocyte growth factor (45). IL-1␤ inhibits VEGF-D expression (46). We showed that FGF-2 inhibits expression of PDGF receptor ␣ transcription (47).…”

NF-κB activation in endothelial cells is critical for the activity of angiostatic agents

“…Together, these data show that anginex, and possibly other angiogenesis inhibitors as well, overcome endothelial cell anergy by activation of the NF-κB pathway. This activity may be shared with the abovementioned proinflammatory cytokines that can have intrinsic antiangiogenesis activities as well (34)(35)(36). Therefore, activation of NF-κB in endothelial cells resulting in stimulation of antitumor immunity can clearly result in an antitumor outcome.…”

“…September 2009 (35), which, depending on the dose, can even induce apoptosis in endothelial cells. Interleukin-1 is mostly known as an angiogenesis stimulator, but some reports identified inhibitory activities as well (36).…”