Effects of Lycopene on Endothelial Protein C Receptor Shedding In Vitro and In Vivo

Abstract

Endothelial protein C receptor (EPCR) plays a pivotal role in augmenting Protein C activation through the thrombin-thrombomodulin complex. EPCR activity is markedly changed by ectodomain cleavage and released as the soluble protein (sEPCR). EPCR shedding is mediated by tumor necrosis factor-α converting enzyme (TACE). Lycopene found in tomatoes and tomato products has anti-oxidant, anti-cancer and anti-inflammatory effects. However, little is known about the effects of lycopene on EPCR shedding. We investigated this issue by monitoring the effects of lycopene on the phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-α, interleukin (IL)-1β and on the cecal ligation and puncture (CLP)-mediated EPCR shedding. Data showed that lycopene potently inhibited the PMA, TNF-α, IL-1β and CLP-induced EPCR shedding by suppressing TACE expression. Furthermore, lycopene reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2 and c-Jun N-terminal kinase (JNK). Given these results, lycopene should be viewed as a candidate therapeutic agent for the treatment of various severe vascular inflammatory diseases via inhibition of the EPCR shedding.