Dipeptidyl peptidase IV reduces trophoblast invasion by inhibiting the activity of MMPs

Abstract

Preeclampsia is a severe pregnancy complication in part due to insufficient implantation. This study aimed at elucidating the mechanism of action of dipeptidyl peptidase IV (DPPIV) in preeclampsia. Small activating RNAs (saRNA) were used to upregulate DPPIV expression in human trophoblast JAR cells. The DPPIV expression level was analyzed by real-time quantitative PCR and western blot and its activity was measured by luminescent protease assay. MMP-9 activity was analyzed by zymography and cell invasion by matrigel invasion assay. DPPIV expression level and activity was significantly increased by saRNA in JAR cells. DDPIV specific inhibitor diprotin A inhibited its activity at both basal and activated levels. DPPIV did not regulate MMP-9 expression but did repress MMP-9 activity. The invading ability of JAR cells was reduced by saRNA but increased by diprotin A. DPPIV might be responsible for the shallow implantation of the placenta due to its inhibition of the invading ability of extravillous trophoblasts, causing preeclampsia at later stage of pregnancy. KEY WORDS: preeclampsia, trophoblast, dipeptidyl peptidase IV, small activating RNA, cell invasion, diprotin APreeclampsia is a severe complication which affects 5-8% of pregnancies and contributes significantly to maternal and fetal morbidity and mortality (Steegers et al., 2010). Moreover, women with preeclampsia have an increased risk of developing cardiovascular disease later in life. Preeclampsia is thought to be resulted from a complex interplay between genetic and environmental factors. Family studies provides the evidence for the involvement of genetic factors, which have shown that daughters and sisters of preeclamptic women have a higher risk of preeclampsia (Nilsson et al., 2004). Moreover, the incidence of preeclampsia is also different among various ethnic groups (Steegers et al., 2010). Unfortunately, the precise etiology of preeclampsia remains unclear after decades of efforts.It is required for a blastocyst to implant into the uterine endometrium to form a functional placenta during the establishment of mammalian pregnancy. A functional placenta formation requires the 'extravillous trophoblast' (EVT) engrafting and remodeling uterine spiral arteries to create placental blood supply at the end of the first trimester (Burton et al., 2010). Shallow or inappropriate implantation and placentation may result in first trimester miscarriage, preeclampsia, and other obstetric complications (Aplin, 2010). The trophoblast invasion is regulated by local endometrial environment that endometrial stromal cells differentiate into decidual Int.

The Importance of Tumor Necrosis Factor-<i>α</i>-Induced Protein-8 Like-2 in the Pathogenesis of Cervical Cancer and Preeclampsia via Regulation of Cell Invasion

“…In order to further uncover the mechanism of TIPE2 in PE, the HTR8/SVneo and JEG3 cells were selected to perform transfection, and as a result, TIPE2 overexpression was found to enhance the invasion abilities of HTR8/SVneo and JET3 cells, with up-regulations of MMP-2 and MMP-9. As we know, MMPs are the major modulators for the degradation of extracellular matrix and play key roles in the invasion of trophoblasts (Li et al 2014b). For example, increasing the activity of MMP-2 and MMP-9 has been confirmed by the previous study to enhance the migration and invasion of trophoblasts .…”

Paternal contribution to the preeclampsia phenotype

“…This study also suggests that the genes controlling 'proteases' are most likely to be essential for extracellular matrix degradation and trophoblast invasion, including MMP2 [51], MMP9 [51], ADAM12 [52], PAPPA [53], ADM2 [54], POFUT1 [55], EDP, CORIN [56], GALNT2 [57], DPP4 [58], PRSS8 [59], HTRA4 [60], and SERPINB5 [61]. These genes were recognized as important factors mediating tumor invasion.…”