Innate immune system stimulation during pregnancy induces upregulation of thromboxane synthesis in rat maternal heart

dc.creatorTucker, Selina
dc.creatorCushen, Spencer
dc.creatorBradshaw, Jessica L.
dc.creatorGardner, Jennifer
dc.creatorRicci, Contessa
dc.creatorDick, Gregory
dc.creatorTune, Johnathan
dc.creatorGoulopoulou, Styliani
dc.creator.orcid0000-0002-7959-8716 (Tucker, Selina)
dc.creator.orcid0000-0003-3784-9190 (Gardner, Jennifer)
dc.description.abstractPurpose: Infections during pregnancy are associated with adverse clinical outcomes. We previously showed that exposure to immunostimulatory ODN2395 (synthetic Toll-like receptor 9 agonist) during pregnancy induces maternal vascular inflammation and enhances vascular tone in pregnant rats. These outcomes were mediated in part by activation of the cyclooxygenase/thromboxane A2 (COX/TxA2) pathway. The objective of this study was to investigate the impact of ODN2395-induced immune system stimulation on maternal hearts during pregnancy. We hypothesize that exposure to TLR9-mediated immune system activation during pregnancy upregulates the COX/TxA2 signaling pathway in maternal cardiac tissues in rats. Methods: Rats were treated with a synthetic CpG DNA (ODN2395, 1 mg/kg, intraperitoneal injection) or vehicle (saline) in late pregnancy. Fetoplacental biometrics were recorded after euthanasia on gestational day 20 and maternal hearts were collected to assess COX-1 and COX-2 expression and 6-keto PGF1α (PGI2 metabolic byproduct) and TxB2 (TxA2 metabolic byproduct) production. Results: Left ventricular tissues from dams treated with ODN2395 released higher concentrations of TxB2 compared to tissues from vehicle-treated dams (ODN2395: 0.56 ± 0.06 ng/mg protein vs. Vehicle: 0.31 ± 0.04 ng/mg protein, n5, p=0.0041) but there were no differences in cardiac 6-keto PGF1α release between groups (p=0.16). COX-2 expression was lower in left ventricles from ODN2395-treated rats compared to vehicle-treated rats (p=0.009). There were no differences in cardiac COX-1 expression between groups (p=0.27). Exposure to ODN2395 during pregnancy increased fetal-placental weight ratio (ODN2395: 5.3 ± 0.22 vs. Vehicle: 4.7 ± 0.15, p = 0.04). COX-2 expression was greater in placental tissues from ODN2395-treated rats (p=0.004) but there were no differences in placental 6-keto PGF1α (p=0.51) and TxB2 release (p=0.32). Conclusion: TLR9 activation during pregnancy induces upregulation of TxB2 synthesis in maternal cardiac tissues coupled with a reduction in COX-2 expression. Maternal heart may have enhanced sensitivity to bacterial infections during pregnancy.
dc.description.sponsorshipNIHR018L146562, 18PRE33960162, T32AG020494, NIH R25GM125587
dc.titleInnate immune system stimulation during pregnancy induces upregulation of thromboxane synthesis in rat maternal heart