Activation of Ca2+-dependent signaling causes postpartum cardiac hypertrophy in rats with gestational diabetes

The incidence of gestational diabetes mellitus is growing due to increasing rates of metabolic syndrome and obesity in the general population and more advanced maternal age. GDM heightens the risk of developing cardiac hypertrophy and dysfunction later in life, but the underlying mechanisms are largely unknown. Here we tested the role of Ca2+-dependent hypertrophy signaling in the structural remodeling of the heart following a GDM-complicated pregnancy. Female rats expressing the human isoform of the pancreatic hormone amylin (HIP rats) were used as a GDM model and WT littermates served as controls. In both groups, glucose tolerance decreased during pregnancy and recovered after giving birth, with HIP females remaining glucose intolerant compared to the WT throughout the study. Cardiac hypertrophy, assessed from heart weight-to-body weight ratio, heart weight-to-tibia length ratio and echocardiographic measurements of the left-ventricular wall, occurred in both HIP and WT females during pregnancy. By two months postpartum, heart size returned to the pre-pregnancy level in the WT but remained significantly larger in HIP females. The activity of calcineurin/NFAT hypertrophy pathway, assessed from the nuclear-to-cytosolic localization of NFATc4, was reduced during late pregnancy in both groups. In WT females, this pathway returned to its baseline activation level within two months postpartum. However, in postpartum HIP females the ratio of nuclear-to-cytosolic NFATc4 was significantly larger than at baseline, indicating activation of this hypertrophy pathway. In contrast, the CaMKII/HDAC hypertrophy signaling was strongly activated in late pregnancy and returned to baseline postpartum in both HIP and WT females. Ca2+ transient decay was slower in myocytes from postpartum HIP females vs. baseline, while no differences occurred in the WT. In summary, two months after a GDM-complicated pregnancy, female rats show cardiac hypertrophy that is likely caused by activation of calcineurin/NFAT hypertrophy pathway.