Mitigation of gestational diabetes-induced endothelial dysfunction through FGF21-NRF2 pathway activation involving L-Cystine

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1870; no. 7; p. 167329
• Main Authors: Sun, Congcong, Wang, Linlin, Huang, Huiya, Zheng, Zhenzhen, Xu, Xiaomin, Wang, Hai, Chen, Kaixin, Li, Xiaoqing, Lai, Yanan, Zhang, Hongping, Chu, Maoping, Zheng, Jianqiong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2024
• Subjects: Adult; Cystine - metabolism; Diabetes, Gestational - metabolism; Endothelial function; Female; Fibroblast growth factor 21; Fibroblast Growth Factors - metabolism; Gestational diabetes mellitus; Glucolipid metabolism disorders; Humans; L-Cystine; NF-E2-Related Factor 2 - metabolism; Nuclear factor erythroid 2-related factor 2; Pregnancy; Signal Transduction - drug effects; Gestational diabetes mellitus; Fibroblast growth factor 21; Endothelial function; L-Cystine; Glucolipid metabolism disorders; Nuclear factor erythroid 2-related factor 2
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167329

Gestational diabetes mellitus (GDM) disrupts glucolipid metabolism, endangering maternal and fetal health. Despite limited research on its pathogenesis and treatments, we conducted a study using serum samples from GDM-diagnosed pregnant women. We performed metabolic sequencing to identify key small molecule metabolites and explored their molecular interactions with FGF21. We also investigated FGF21's impact on GDM using blood samples from affected women. Our analysis revealed a novel finding: elevated levels of L-Cystine in GDM patients. Furthermore, we observed a positive correlation between L-Cystine and FGF21 levels, and found that L-Cystine induces NRF2 expression via FGF21 for a period of 96 h. Under high glucose (HG) conditions, FGF21 upregulates NRF2 and downstream genes NQO1 and EPHX1 via AKT phosphorylation induced by activation of IRS1, enhancing endothelial function. Additionally, we confirmed that levels of FGF21, L-Cystine, and endothelial function at the third trimester were effectively enhanced through appropriate exercise and diet during pregnancy in GDM patients (GDM + ED). These findings suggest FGF21 as a potential therapeutic agent for GDM, particularly in protecting endothelial cells. Moreover, elevated L-Cystine via appropriate exercise and diet might be a potential strategy to enhance FGF21's efficacy. The schematic diagram illustrates the protective effect of FGF21 on HUVEC under high sugar conditions. A hyperglycemic environment can induce functional damage and oxidative stress to placental endothelial cells, impairing their function and leading to apoptosis. This study revealed that L-Cystine (induced by exercise and diet) could enhance endogenous expression of FGF21 and NRF2, but did not significantly improve cell phenotype. Adequate exogenous FGF21 and endogenous FGF21 can regulate NRF2 by promoting AKT phosphorylation through IRS1, facilitating its nuclear translocation, and transcription of downstream antioxidant genes (EPHX1, NQO1, AKR1A1, et al), thereby inhibiting the production of ROS and HUVECs apoptosis while promoting HUVECs migration to ameliorate endothelial function and angiogenesis. [Display omitted] •L-Cystine modestly up-regulates FGF21 under HG induced stress, improving endothelial dysfunction over a prolonged period.•Adequate exogenous FGF21 prevents GDM-induced endothelial dysfunction and confers resistance against oxidative stress.•Nrf2 plays a pivotal role in the improvement of endothelial function by FGF21 under GDM conditions.•FGF21 modulates the nuclear localization of Nrf2 under high glucose conditions through IRS1/Akt signaling pathway.•Proper exercise and diet during pregnancy effectively enhance FGF21 and L-Cystine in GDM patients at the second trimester.