Dysregulated non-coding telomerase RNA component and associated exonuclease XRN1 in leucocytes from women developing preeclampsia-possible link to enhanced senescence

Abstract

Senescence in placenta/fetal membranes is a normal phenomenon linked to term parturition. However, excessive senescence which may be induced by telomere attrition, has been associated with preeclampsia (PE). We hypothesized that the telomerase complex in peripheral blood mononuclear cells (PBMC) and circulating telomere associated senescence markers would be dysregulated in women with PE. We measured long non-coding (nc) RNA telomerase RNA component (TERC) and RNAs involved in the maturation of TERC in PBMC, and the expression of TERC and 5′–3′ Exoribonuclease 1 (XRN1) in extracellular vesicles at 22–24 weeks, 36–38 weeks and, 5-year follow-up in controls and PE. We also measured telomere length at 22–24 weeks and 5-year follow-up. The circulating senescence markers cathelicidin antimicrobial peptide (CAMP), β-galactosidase, stathmin 1 (STMN1) and chitotriosidase/CHIT1 were measured at 14–16, 22–24, 36–38 weeks and at 5-year follow-up in the STORK study and before delivery and 6 months post-partum in the ACUTE PE study. We found decreased expression of TERC in PBMC early in pregnant women who subsequently developed PE. XRN1 involved in the maturation of TERC was also reduced in pregnancy and 5-year follow-up. Further, we found that the senescence markers CAMP and β-galactosidase were increased in PE pregnancies, and CAMP remained higher at 5-year follow-up. β-galactosidase was associated with atherogenic lipid ratios during pregnancy and at 5-year follow-up, in PE particularly. This study suggests a potential involvement of dysfunctional telomerase biology in the pathophysiology of PE, which is not restricted to the placenta.

OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: Sperm telomeres, oxidative stress, and infertility

“…A recent review revealed clear associations between relative telomere length/integrity and male/female fertility factors (Vasilopoulos et al 2019). In this review, we have identified any additional clinical investigations since the Vasilopoulos paper and characterized them in the same manner as previously reported (Darmishonnejad et al 2019, Santana et al 2019, Tahamtan et al 2019, Berneau et al 2020, Huang et al 2020, Laurentino et al 2020, Pedroso et al 2020, Weeg et al 2020, Amirzadegan et al 2021, Berby et al 2021, Gentiluomo et al 2021, Lekva et al 2021, M'kacher et al 2021, Purdue-Smithe et al 2021, Rocca et al 2021, Lara-Cerrillo et al 2022, Michaeli et al 2022, Piani et al 2022. A visualization of the associations of relative telomere length with known male/female fertility factors from all aforementioned clinical investigations can be found in Fig.…”

Gene Expression Network Analysis Identifies Potential Targets for Prevention of Preeclampsia

“…20 At the molecular level, the microRNA spectrum of blood exosomes has been used to evaluate the pathophysiology of preeclampsia and predict the disease, 21 and there are more and more studies at gene level. [22][23][24][25] Zhang and Horvath 26 conducted the first WGCNA analysis in 2005 and then published WGCNA R software package in R based on theory of the research method in 2008. As an efficient and accurate bioinformatics approach, WGCNA has been widely used for the gene network analysis.…”

Increased ferroptosis in leukocytes from preeclamptic women involving the long non‐coding taurine upregulated gene 1 (TUG1)

“…In the current study, additional exclusion criteria included gestational diabetes mellitus. A substudy [27] including 215 normotensive controls and 38 PE women were included in this study, and women developing gestational diabetes were excluded to reduce the heterogeneity in the control group. In the ACUTE-PE study, there were 34 PE and 61 control subjects.…”

“…Deconvolution of cell-type proportions from the previous microarray data [27] was performed with CIBERSORTx using the validated LM22 signa-ture as Ref. [30].…”