Glutaredoxin-1 overexpression induces hypertensive pregnancy and maternal cardiac fibrosis

Elevation of oxidative stress is explicitly linked to hypertensive pregnancies with high levels measurable in the maternal circulation. Hypertensive pregnancies lead to life-long risk of cardiac dysfunction, yet the underpinning molecular pathway are unknown. Oxidative stress modify proteins via oxidative post-translational modifications (ox-PTMs) which can regulate intracellular signalling by either potentiating or inhibiting protein activity. One of these, S-glutathionylation is a common oxPTM reversed by glutaredoxin (Glrx). We aimed to investigate the role of Glrx in a murine model of pregnancy combining physiological in vivo cardiac dynamics with histological assessment of maternal organs, to identify how perturbation of redox signalling can lead to cause pregnancy-induced cardiovascular complications. Mice overexpressing Glrx(Glrx-TG) and littermate controls (WT) underwent timed pregnancy. Left-ventricle (LV) pressure-volume (PV) loops was measured on day 18.5 by catheter inserted into LV. Pregnancy outcome and maternal organ pathology was conducted. At day 18.5 of pregnancy Glrx-TG mice had higher aortic blood pressure, with more incidents of fetal reabsorptions compared to WT. End-systolic pressure assessed from PV-loops showed a trend for increase in TG vs WT, although there was no overall effect on cardiac ejection fraction or stroke-volume. Interestingly, TG LV appeared to have higher contractility (End-systolic PV relationship). TG mice had an increase in cardiomyocyte size with no change in capillary density. Moreover, there was a significant increase in cardiac and renal fibrosis in Glrx-TG mothers. Further studies will be needed to identify the redox sensitive molecular pathways, that are altered by Glrx overexpression in the maternal cardiovascular system.