Zingerone suppresses the shedding of endothelial Protein C receptor

Zingerone (ZGR), a phenolic alkanone found in Zingiber officinale, has been reported to have various pharmacological activities including anti-inflammatory and anti-apoptotic activities. The endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway and activation of protein C. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). However, little is known about the effects of ZGR on EPCR shedding. We investigated this by monitoring the effects of ZGR on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-mediated EPCR shedding in mice, as well as by analyzing the underlying mechanisms. Here, ZGR triggered potent inhibition of PMA-, TNF-α-, IL-1β-and CLP-induced EPCR shedding through the inhibition of phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38, janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2. ZGR also inhibited PMA-induced TACE expression and activity in HUVECs, suggesting that p38, ERK1/2, and JNK could be molecular targets of ZGR. These results demonstrate the potential of ZGR as an agent against PMA- and CLP-mediated EPCR shedding.