Epigenetic Down-Regulation of Sirt 1 via DNA Methylation and Oxidative Stress Signaling Contributes to the Gestational Diabetes Mellitus-Induced Fetal Programming of Heart Ischemia-Sensitive Phenotype in Late Life

Liu²,

et al. 2019

Exp Ther Med

Expression and correlation of Chemerin and fatty acid-binding protein 4 (FABP4) in peripheral blood of gestational diabetes mellitus (GDM) patients were investigated. Sixty patients with GDM from March 2018 to March 2019 in the People's Hospital of Zhangqiu Area were selected as the study group (SG) and another 50 healthy pregnant women corresponding to their age and pregnancy were selected as the control group (CG). Enzyme linked immunosorbent assay (ELISA) was used to detect the expression of Chemerin and FABP4 in serum. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of Chemerin and FABP4 in peripheral blood for GDM patients. Pearson's correlation coefficient was used to analyze the correlation between Chemerin and FABP4 and the correlation between Chemerin and inflammatory factors such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Expression of Chemerin and FABP4 in peripheral blood of GDM patients were significantly higher than those in CG. The AUC of GDM patients diagnosed with Chemerin and FABP4 in peripheral blood was 0.820 and 0.814, while the AUC of GDM patients diagnosed with Chemerin combined with FABP4 in peripheral blood was 0.904. Expression of inflammatory factors IL-6 and TNF-α in the SG were significantly higher than those in the CG. Chemerin in the SG was positively correlated with FABP4 and positively correlated with inflammatory factors IL-6 and TNF-α. Patients with advanced age (≥35 years), family history of diabetes, hyperlipidemia, high pre-pregnancy BMI, high fasting blood glucose, high Chemerin and high FABP4 expression have high risk of GDM. In conclusion, Chemerin and FABP4 were upregulated in the peripheral blood of GDM patients. There was a positive correlation between the two and a positive correlation with the inflammatory factors IL-6 and TNF-α.

Section: Discussionmentioning

confidence: 99%

Expression and correlation of Chemerin and FABP4 in peripheral blood of gestational diabetes mellitus patients

Liu²,

et al. 2019

Exp Ther Med

“…48 Our work also validates the previous findings that SIRT-1 is a key pathway affected by GDM. 49 Furthermore, we demonstrated in relevant in vitro models that FKBPL and SIRT-1 proteins are reduced in both the presence of hyperglycaemia and low oxygen tension that could have adverse effects on trophoblast function and placental development 31 .…”

Section: Discussionmentioning

confidence: 89%

FKBPL and SIRT-1, key angiogenesis proteins, are downregulated by diabetes in pregnancy

Alqudah

Eastwood

Jerotić

et al. 2020

Preprint

Context Diabetes in pregnancy is associated with numerous complications, however the mechanisms are still poorly understood. Objective To investigate the role of new angiogenesis markers, FKBPL and SIRT-1, in pre-gestational (type 1 diabetes, T1D) and gestational diabetes (GDM). Design and intervention Placental FKBPL, SIRT-1, PlGF and VEGF-R1 protein expression was determined from pregnant women with GDM or T1D, and in first trimester trophoblast cells exposed to high glucose and varying oxygen concentrations. Endothelial cell function was assessed in high glucose conditions and FKBPL overexpression. Settings and Participants Human placental samples from pregnant women with GDM (n=6) or T1D (n=8) were collected to assess FKBPL and SIRT-1 protein expression compared to non-diabetic controls. Main outcome measures To determine the role of placental FKBPL and/or SIRT-1 in diabetic pregnancies, in first trimester trophoblasts and endothelial cell function in high-glucose environment. Results Placental FKBPL protein expression was downregulated in T1D (FKBPL; p<0.05) whereas PlGF/VEGF-R1 were upregulated (p<0.05); correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 (p<0.001) was significantly downregulated even when adjusted for gestational age (r=-0.92, p=0.001). FKBPL and SIRT-1 were also downregulated in ACH-3P cells in high glucose conditions and 6.5%/2.5% oxygen concentrations (p<0.05). FKBPL overexpression in HUVECs reduced tubule formation compared to empty vector control, in high glucose conditions (junctions; p<0.01, branches; p<0.05). Conclusions FKBPL and/or SIRT-1 downregulation in response to diabetes may have a role in the development of vascular dysfunction in pregnancy, and associated complications such as preeclampsia.

“…The offspring rats (~3 month-old) were subjected to myocardial ischemia-reperfusion in vivo as described previously 22 . Briefly, rats were anesthetized with isoflurane (5% for induction, 3% for maintenance) (Vet ONE, USA) mixed with oxygen (2 L/min for induction, 1 L/min for maintenance) by inhalation and placed on the RoVent Jr. Small Animal Ventilator (Kent Scientific).…”

Section: Methodsmentioning

confidence: 99%

Reprogramming of miR-181a/DNA methylation patterns contribute to the maternal nicotine exposure-induced fetal programming of cardiac ischemia-sensitive phenotype in postnatal life

Jian¹,

Zhang²,

Li³

et al. 2020

Theranostics

Self Cite

Background: E-cigarette and other novel electronic nicotine delivery systems (ENDS) have recently entered the market at a rapid pace. The community desperately needs answers about the health effects of ENDS. The present study tested the hypothesis that perinatal nicotine exposure (PNE) causes a gender-dependent increase in vulnerability of the heart to ischemia-reperfusion (I/R) injury and cardiac dysfunction in male rat offspring via reprogramming of the miRNA-181a (miR-181a)-mediated signaling pathway and that miR-181a antisense could rescue this phenotype. Methods: Nicotine or saline was administered to pregnant rats via subcutaneous osmotic minipumps from gestational day 4 until postnatal day 10. Cardiac function and molecular biological experiments were conducted in ~3- month-old offspring. Results: PNE enhanced I/R-induced cardiac dysfunction and infarction in adult male but not in female offspring, which was associated with miR-181a over-expression in left ventricle tissues. In addition, PNE enhanced offspring cardiac angiotensin receptor (ATR) expressions via specific CpG hypomethylation of AT 1 R/AT 2 R promoter. Furthermore, PNE attenuated cardiac lncRNA H19 levels, but up-regulated cardiac TGF-β/Smads family proteins and consequently up-regulated autophagy-related protein (Atg-5, beclin-1, LC3 II, p62) expression in the male offspring. Of importance, treatment with miR-181a antisense eliminated the PNE's effect on miR-181a expression/H19 levels and reversed PNE-mediated I/R-induced cardiac infarction and dysfunction in male offspring. Furthermore, miR-181a antisense also attenuated the effect of PNE on AT 1 R/AT 2 R/TGF-β/Smads/autophagy-related biomarkers in the male offspring. Conclusion: Our data suggest that PNE could induce a reprogramming of cardiac miR-181a expression/DNA methylation pattern, which epigenetically modulates ATR/TGF-β/autophagy signaling pathways, leading to gender-dependent development of ischemia-sensitive phenotype in postnatal life. Furthermore, miR-181a could severe as a potential therapeutic target for rescuing this phenotype.