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.
Highlights
Pregnancy is a state of oxidative stress as the higher metabolic demand of the growing fetus results in increased reactive oxygen species production[1,2]
To further explore these novel data we measured 1) levels of ncRNA telomerase RNA component (TERC) and other mRNAs involved in the maturation of TERC in peripheral blood mononuclear cells (PBMC) and extracellular vesicles at different time points during pregnancy, in term placenta, and at 5-year follow-up comparing PE and controls; 2) telomere length during pregnancy and at 5-year follow-up in PE and controls; 3) levels of the senescence markers cathelicidin antimicrobial peptide (CAMP), β-galactosidase, stathmin 1 (STMN1), and chitotriosidase/CHIT1 in two independent cohorts at different timepoints during pregnancy and at follow-up comparing PE and controls; and 4) evaluated if these senescence markers were associated with future risk of cardiovascular disease (CVD) as evaluated by atherogenic lipid ratios and arterial stiffness 5 years post-partum in women with PE and controls
We investigated the temporal course and follow-up levels of TERC and some of the mRNAs involved in the maturation of TERC (DCP2, XRN1, NCBP1, PABPN1, MTREX/MTR4) (Fig. 1B)
Summary
Pregnancy is a state of oxidative stress as the higher metabolic demand of the growing fetus results in increased reactive oxygen species production[1,2]. In a pilot array from 22 to 24 weeks’ gestation in peripheral blood mononuclear cells (PBMC), including lymphocytes, monocytes, natural killer cells and dendritic cells, from women who subsequently developed PE and normotensive controls, we found lower ncRNA TERC in the PE women, suggesting dysfunctional telomerase biology To further explore these novel data we measured 1) levels of ncRNA TERC and other mRNAs involved in the maturation of TERC in PBMC and extracellular vesicles at different time points during pregnancy, in term placenta, and at 5-year follow-up comparing PE and controls; 2) telomere length during pregnancy and at 5-year follow-up in PE and controls; 3) levels of the senescence markers cathelicidin antimicrobial peptide (CAMP), β-galactosidase, stathmin 1 (STMN1), and chitotriosidase/CHIT1 in two independent cohorts at different timepoints during pregnancy and at follow-up comparing PE and controls; and 4) evaluated if these senescence markers were associated with future risk of CVD as evaluated by atherogenic lipid ratios and arterial stiffness 5 years post-partum in women with PE and controls
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