title: Rosmarinic acid down-regulates endothelial protein C receptor shedding in vitro and in vivo.
abstract: 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.
authors.affiliation: Department of Anatomy and Histology, College of Oriental Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Yang
authors.forename: Kyung-Sik
authors.initials: KS
authors.lastname: Song
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology / Q000627:therapeutic use*; D053630:Depsides / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D000074283:Endothelial Protein C Receptor; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D012995:Solubility; D000097123:Rosmarinic Acid
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D002934:Cinnamates; D053630:Depsides; D000074283:Endothelial Protein C Receptor; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D000097123:Rosmarinic Acid; C478370:PROCR protein, human; C080248:Procr protein, mouse; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
keywords: CLP; EPCR; PMA; Rosmarinic acid; Shedding