title: Suppressive effects of polyozellin on endothelial protein C receptor shedding via inhibiting TACE activity and MAP kinases.
abstract: Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). Polyozellin, a major constituent of a Korea edible mushroom Polyozellus multiplex, has been known to exhibit the biological activities such as anti-oxidative and anti-inflammatory effects. However, little is known about the effects of polyozellin on EPCR shedding. We investigated this issue by monitoring the effects of polyozellin on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-α-, interleukin (IL)-1β-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-mediated EPCR shedding in mice and underlying mechanism. Data demonstrate that polyozellin induced potent inhibition of PMA-, TNF-α-, IL-1β- (in HUVECs), and CLP-induced EPCR shedding (in mice) via inhibition of phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38, janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2. Polyozellin also inhibited the expression and activity of PMA-induced TACE in HUVECs suggesting that p38, ERK1/2, and JNK could be the molecular targets of POZ. These results demonstrate the potential of polyozellin as an anti-EPCR shedding reagent against PMA-mediated and CLP-mediated EPCR shedding.
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea; Department of Biochemistry and Cell Biology, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Lee
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, School of Medicine, Kyungpook National University, Daegu 700-721, Republic of Korea. Electronic address: sarasate2222@gmail.com.
authors.forename: Dong Ho
authors.initials: DH
authors.lastname: Park
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea. Electronic address: baejs@knu.ac.kr.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000363:Agaricales / Q000737:chemistry*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D004195:Disease Models, Animal; D000074283:Endothelial Protein C Receptor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005663:Furans / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D005663:Furans; D053583:Interleukin-1beta; C478370:PROCR protein, human; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; C109015:polyozellin; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D013755:Tetradecanoylphorbol Acetate
keywords: CLP; EPCR shedding; Polyozellin; Vascular inflammation