Vitamin E regulates bovine granulosa cell apoptosis via NRF2‐mediated defence mechanism by activating PI3K/AKT and ERK1/2 signalling pathways

Abstract

High-yield dairy cows are usually subject to high-intensive cell metabolism and produce excessive reactive oxygen species (ROS). Once ROS is beyond the threshold of scavenging ability, it can induce oxidative stress, imperilling the reproductive performance of cows. The study was to investigate the effects of vitamin E (VE) on H 2 O 2 -induced proliferation and apoptosis of bovine granulosa cells and the underlying molecular mechanism. Granulosa cells were pretreated with VE for 24 hr and then treated with H 2 O 2 for 6 hr. The results showed that VE treatment decreased the intracellular ROS levels, increased the MDA content, and improved the antioxidant enzyme activity in a dose-dependent manner. Furthermore, VE treatment promoted the proliferation and inhibited apoptosis in granulosa cells by up-regulation of CCND1 and BCL2 levels and down-regulation of P21, BAX, and CASP3 levels. The cytoprotective effects of VE were attributed to the activation of the NRF2 signalling pathway. Knockdown of the NRF2 impaired the cytoprotective effects of VE on granulosa cells. Besides, the PI3K/AKT and ERK1/2, but not the p38 signalling pathway is involved in the regulation of VE-mediated cell proliferation and apoptosis. The PI3K/AKT inhibitor LY294002 and ERK1/2 inhibitor SCH772984 inhibited the VE-induced granulosa cell proliferation and promoted apoptosis, whereas the p38 inhibitor SB203580 had the opposite effects. These results were confirmed by proliferation and apoptosis-related gene expression at mRNA and protein levels.The results also showed that the PI3K/AKT inhibitor LY294002 and ERK1/2 inhibitor SCH772984 inhibited VE-induced NRF2, GCLC, GCLM, and HO-1 expression, whereas the p38 inhibitor SB203580 not. Overall, the results demonstrated that VE-regulated granulosa cell proliferation and apoptosis via NRF2-mediated defence system by activating the PI3K/AKT and ERK1/2 signalling pathway.

Kurarinone attenuates hydrogen peroxide‐induced oxidative stress and apoptosis through activating the PI3K/Akt signaling by upregulating IGF1 expression in human ovarian granulosa cells

“…The PI3K/Akt signaling is associated with granulosa cell survival and death 5,44 . Multiple evidences have confirmed that activated PI3K/Akt pathway attenuated H 2 O 2 ‐induced oxidative stress and apoptosis in granulosa cells 25,43,45 . In this study, we found that IGF1 functioned as a classic upstream factor of the PI3K/Akt pathway, and kurarinone augmented the activation of this signaling through directly upregulating IGF1 expression.…”

“…17 oxidative stress and apoptosis in granulosa cells. 25,43,45 In this study, we found that IGF1 functioned as a classic upstream factor of the PI3K/Akt pathway, and kurarinone augmented the activation of this signaling through directly upregulating IGF1 expression. Thus, we deduced that kurarinone targeted IGF1 to increase PI3K/Akt activation, protecting against H 2 O 2 -induced granulosa cell damage.…”

Identification of Key Genes Associated With Early Calf-Hood Nutrition in Subcutaneous and Visceral Adipose Tissues by Co-Expression Analysis

“…The other hub gene, AKT1 , is a key component of AKT/PI3K signaling pathways, which regulate a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis. For example, AKT1 could regulate bovine granulosa cell apoptosis via PI3K/AKT and ERK1/2 signaling pathways to affect the reproductive performance of cows ( 51 ). The previous study also revealed that enhanced nutrition during early calfhood facilitates reproductive performance by regulating the hormones in the hypothalamic-pituitary-ovarian (HPO) axis ( 23 ).…”

Disruption of O-GlcNAcylation Homeostasis Induced Ovarian Granulosa Cell Injury in Bovine

“…During follicular development, GC proliferation and apoptosis play a critical role in maintaining oocyte growth and ovarian functions [ 33 ]. There is accumulating evidence that the disturbance of O-GlcNAc regulation may induce alterations in the cell cycle and cellular proliferation [ 27 ].…”