Exendin-4 inhibits endothelial protein C receptor shedding in vitro and in vivo.

Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, has been reported to attenuate myocardial ischemia and reperfusion (I/R) injury, inflammatory and oxidative responses. Increasing evidence has demonstrated that beyond its role in activation of protein C, endothelial cell protein C receptor (EPCR) is involved in vascular inflammation. EPCR activity is markedly decreased by ectodomain cleavage and release as the soluble EPCR. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). However, little is known about the effects of EX4 on EPCR shedding. Data from this study showed that EX4 induced potent inhibition of phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-induced EPCR shedding in mice. EX4 also inhibited expression and activity of TACE induced by PMA in HUVECs. In addition, treatment with EX4 resulted in reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate the potential of EX4 as an anti-sEPCR shedding reagent against PMA and CLP-mediated EPCR shedding.