Placental Ras Regulates Inflammation Associated with Maternal Obesity

Abstract

Heightened placental inflammation and dysfunction are commonly associated in pregnant obese women compared to their pregnant lean counterparts. The small GTPase superfamily members known as the rat sarcoma viral oncogene homolog (Ras) proteins, in particular, the K-Ras and H-Ras isoforms, have been implicated to regulate inflammation. The aims were to determine the placental Ras expression and activity with maternal obesity and its role in regulating placental inflammation. Human placenta was obtained at term Caesarean section from lean and obese pregnant women to determine the effect of maternal obesity on Ras protein expression and activity. To determine the effect of Ras on inflammation induced by bacterial endotoxin LPS and proinflammatory cytokines TNF-α or IL-1β, the chemical inhibitor lonafarnib (total Ras inhibitor) and siRNA (siKRAS and siHRAS) were used. Total Ras protein expression together with combined K-Ras and H-Ras activity was significantly increased in the placenta of obese pregnant women and when stimulated with LPS, IL-1β, or TNF-α. Lonafarnib significantly suppressed LPS-, IL-1β-, or TNF-α-induced IL-6, IL-8, MCP-1, and GRO-α expression and secretion in placental tissue. Primary trophoblast cells transfected with siKRAS or siHRAS demonstrated only K-Ras silencing significantly decreased IL-1β-, TNF-α-, or LPS-induced IL-6, IL-8, and MCP-1 expression and secretion. Furthermore, siKRAS significantly reduced downstream ERK-1/2 activation induced by LPS. In trophoblast cells, ERK-1/2 signalling is required for IL-6, IL-8, MCP-1, and GRO-α secretion. These studies implicate a role for K-Ras in regulating inflammation in human placenta. Suppressing overactive placental K-Ras function may prevent adverse fetal outcomes complicated by maternal obesity.

Factors associated with neonatal hypoxic ischemic encephalopathy in infants with an umbilical artery pH less than 7.00

“…Pathologic examination of the placenta in the HIE cases could have added interesting information, in particular on the pathophysiological mechanisms leading to HIE. High maternal BMI and smoking during pregnancy can indeed be associated with placental dysfunction and particularly endothelial dysfunction (22) (23), and this dysfunction could lead to chronic hypoxemia, and impair neurological neonatal outcomes.…”

Maternal obesity: new placental paradigms unfolded

“…This cytokine profile is driven by several inflammatory pathways, including the activation of receptors for advanced glycation end-products (RAGEs) by AGEs [61] and activation of Toll-like receptor 4 (TLR4) by NEFAs [60]. In turn, these pathways promote nuclear factor kappa light chain enhancer of activated B cells (NF-κB), the c-Jun N-terminal kinase (JNK), and rat sarcoma virus (Ras) signaling, leading to increased generation of reactive oxygen species (ROS) and the secretion of proinflammatory cytokines such as IL-6, IL-8, MCP-1, tumor necrosis factor α (TNF-α), and IL-1β [62]. Interestingly, a randomized double-blind controlled trial showed that ω3 supplementation in early obese pregnancy prevented the obesityassociated increase in TLR4 signaling and led to a shift in the cytokine profile, indicating that PUFAs are beneficial for healthy placental function [63].…”

“…Although levels of both the saturated fatty acid palmitate and the monounsaturated fatty acid oleate are elevated in obese pregnant women [113], only exposure to palmitate facilitated the development of ER stress in the syncytiotrophoblast, driving translocation of ATF4 and downstream apoptosis mediated by C/EBP homologous protein (CHOP). Furthermore, increased placental palmitate content drives a potent inflammatory response in the obese placenta, including activation of the inflammasome and secretion of inflammatory cytokines [62,114]. This inflammatory response is likely to form a reciprocal cause-and-effect relationship with placental ER stress [91,104,115,116].…”

Autophagy Process in Trophoblast Cells Invasion and Differentiation: Similitude and Differences With Cancer Cells

“…Also, trophoblast cells such as CTB, STB, and EVT encode for a Receptor Tyrosine Kinase (RTK), namely c-erbB2 (HER2/neu, ERBB2), c-fms (CSF1R), c-met (MET) and c-kit (KIT) (64-67), as well as for transcription factors that have been implicated in trophoblast invasion such as c-fos (FOS) and c-jun (JUN), in addition to c-myc (MYC) and c-ets1 (ETS) (68)(69)(70)(71). Additionally, in iEVT, c-sis (SIS, Platelet-derived Growth Factor Beta (PDGFB)) is expressed, which encodes for one of the two chains (the B-chains) constituting Platelet-derived Growth Factor (PDGF) (72) and in EVT the c-ras family (Kirsten rat Sarcoma viral oncogene (K-RAS), Neuroblastoma RAS viral oncogene homolog (N-RAS), and Harvey rat sarcoma (H-RAS)) is expressed encoding for Rat sarcoma (RAS) proteins that regulate cellular proliferation and inflammation in the human placenta (73,74). All the aforementioned proto-oncogenes are crucial in the first step of malignant transformation and its physiological expression occurs during the first week of pregnancy promoting proliferation, migration, and invasion of the trophoblast (2).…”