Abstract P2009: Mice Lacking S-nitrosoglutathione Reductase (gsnor ^-/- ), A Mouse Model Of Preeclampsia, Exhibit Abnormal Calcium Regulation And Cardiac Hypertrophy During Pregnancy.

Introduction: We recently showed that mice lacking S-nitrosoglutathione reductase (GSNOR -/- mice), a denitrosylase that regulates protein S-nitrosylation, exhibit the clinical features of preeclampsia (PE) a leading cause of maternal mortality. PE predisposes the mother to increased risk of cardiovascular (CV) injury later in life and is linked to cardiac hypertrophy and impaired relaxation. Cardiac hypertrophy and relaxation are regulated by calcium cycling. We hypothesized that GSNOR deficiency in pregnant mice alters calcium cycling, leading to hypertrophy and impaired cardiac relaxation. Methods: Pregnant control (WT [C57B6]) and GSNOR -/- mice were examined at non-pregnant (NP) and late pregnancy (17.5 dpc). Cardiomyocytes (CMs) (N=3-4 mice/group; n=8-24 CMs/heart) were isolated and assessed for intracellular calcium and sarcomere shortening using IonOptix system. Dynamic parameters associated with calcium decay and sarcomere relaxation were recorded (time to peak (ttp), time to 50% of baseline (tt50%); d SL/ d t min , time to d [Ca]/ d t min , etc.). Experiments were conducted at 37°C. Results: At late pregnancy, systolic calcium levels were significantly elevated in CMs isolated from GSNOR -/- as compared to WT mothers. Despite the increased cytosolic calcium, CMs from pregnant GSNOR -/- mice exhibited no change in contractility. The improved calcium decay rate observed in CMs from pregnant versus NP WT mice, was absent in GSNOR -/- mothers. Similarly, sarcomere relaxation parameters and sarcomere resting length, which were also improved by pregnancy in WT CMs, were impaired in CMs from pregnant versus NP GSNOR -/- mice. In addition, hearts were significantly enlarged in GSNOR -/- mothers as compared to WT, even when normalized to tibia length. Conclusion: The elevated systolic calcium levels, impaired cardiac relaxation, and cardiac hypertrophy seen in pregnant GSNOR -/- mice may predisposes them to higher risk for CV injury during pregnancy and later in life.