Rosmarinic acid down-regulates endothelial protein C receptor shedding in vitro and in vivo

• Published in: Food and chemical toxicology 2013-09, Vol.59, p.311-315
• Main Authors: Ku, Sae-Kwang, Yang, Eun-Ju, Song, Kyung-Sik, Bae, Jong-Sup
• Format: Article
• Language: English
• Subjects: ADAM Proteins - antagonists & inhibitors; ADAM Proteins - metabolism; ADAM17 Protein; Animals; anti-inflammatory activity; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antigens, CD - chemistry; Antigens, CD - metabolism; Biological and medical sciences; Cells, Cultured; Cinnamates - pharmacology; Cinnamates - therapeutic use; CLP; coagulation; Depsides - pharmacology; Depsides - therapeutic use; Disease Models, Animal; Down-Regulation - drug effects; Endothelial Protein C Receptor; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - immunology; Endothelium, Vascular - metabolism; EPCR; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - immunology; Human Umbilical Vein Endothelial Cells - metabolism; Humans; inflammation; interleukin-1beta; leaves; Male; MAP Kinase Signaling System - drug effects; Medical sciences; Mice; Mice, Inbred C57BL; mitogen-activated protein kinase; monitoring; Peptide Fragments - blood; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Perilla frutescens; phosphorylation; Phosphorylation - drug effects; PMA; Protein Processing, Post-Translational - drug effects; Proteolysis; Receptors, Cell Surface - blood; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - metabolism; Rosmarinic Acid; Sepsis - blood; Sepsis - drug therapy; Sepsis - immunology; Sepsis - metabolism; Shedding; Solubility; Toxicology; tumor necrosis factor-alpha
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2013.06.003

•EPCR shedding is involved in the vascular inflammation.•EPCR shedding is mediated by PMA activation.•RA inhibited the PMA and CLP-induced EPCR shedding by suppressing TACE expression.•RA reduced PMA-stimulated phosphorylation of p38, ERK1/2 and JNK. The endothelial protein C receptor (EPCR) plays pivotal roles in coagulation and inflammation, however, its activity is markedly changed by ectodomain cleavage and release as the soluble protein (sEPCR). According to previous studies, there are approximately 100ng/ml sEPCR in human plasma and the levels increase in inflammatory diseases. EPCR can be shed from the cell surface, and this is mediated by tumor necrosis factor-α converting enzyme (TACE). We recently reported on the anti-inflammatory and barrier protective activities of rosmarinic acid (RA), an important component of the leaves of Perilla frutescens. However, little is known about the effects of RA on EPCR shedding. Here, we investigated this issue by monitoring the effects of RA on phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β, and on cecal ligation and puncture (CLP)-mediated EPCR shedding and underlying mechanisms. Data showed that treatment with RA resulted in potent inhibition of PMA, TNF-α, IL-induced EPCR shedding by suppression of TACE expression. In addition, RA reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results suggest the potential for use of RA as an anti-sEPCR shedding reagent against PMA, TNF-α, IL-1β and CLP-mediated EPCR shedding.