title: Withaferin A is an inhibitor of endothelial protein C receptor shedding in vitro and in vivo.
abstract: Withaferin A (WFA), an active compound from Withania somnifera, has been widely researched for its anti-inflammatory and cardioactive properties and effects on the central nervous system. The endothelial cell protein C receptor (EPCR) plays important roles in blood coagulation and inflammation. EPCR activity is markedly changed by ectodomain cleavage and release as the soluble EPCR. EPCR is shed from the cell surface, mediated by tumor necrosis factor-α converting enzyme (TACE). In this study, we investigated the effects of WFA on the EPCR shedding in human umbilical vein endothelial cells (HUVECs) and in mice and the associated signaling pathways. WFA was found to induce inhibition of phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and on cecal ligation and puncture (CLP)-induced EPCR shedding and WFA suppressed the expression and activity of TACE. In addition, treatment with WFA resulted in reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate a therapeutic potentiality of WFA as an anti-sEPCR shedding reagent against PMA and CLP-mediated EPCR shedding.
authors.affiliation: Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu Fatima Hospital, Daegu 701-724, Republic of Korea.
authors.forename: Min-Su
authors.initials: MS
authors.lastname: Han
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 / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D054358:Withanolides / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001779:Blood Coagulation Factors; D053583:Interleukin-1beta; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D054358:Withanolides; C091963:activated protein C receptor; C016658:phorbolol myristate acetate; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C009684:withaferin A; D013755:Tetradecanoylphorbol Acetate
keywords: CLP; EPCR shedding; PMA; Withaferin A