Abstract 15371: Mice Lacking S-Nitrosoglutathione Reductase (GSNOR -/- ), a Mouse Model of Preeclampsia, Exhibited Nitroso-Redox Imbalance and Deterioration of Cardiovascular Structure and Function in Postpartum Mothers

Abstract

Introduction: Preeclampsia (PE), a leading cause of maternal mortality, is linked to persistent pathological changes in the heart, predisposing the mother to increased risk of chronic cardiovascular (CV) disease later in life. PE is characterized by increased S-nitrosylated (SNO) proteins and nitroso-redox imbalance. We recently showed that mice lacking S-nitrosoglutathione reductase (GSNOR -/- mice), a denitrosylase that regulates protein S-nitrosylation, exhibit the clinical features of PE including maternal hypertension, blunted increase in cardiac output, abnormal remodeling of left ventricular (LV) cardiac structure, dysregulation in nitrosylation and nitroso-redox imbalance. Hypothesis: The nitroso-redox imbalance seen during pregnancy in GSNOR -/- mice persists in postpartum (PP), leading to increased maternal susceptibility to CV injury. Methods: Pregnant control (WT [C57Bl/6J]) and GSNOR -/- mice (N=5) were examined at baseline, late-stage pregnancy (17.5 dpc) and 6 weeks PP. LV structure, cardiac output and stroke volume were determined using echocardiography (Vevo 2100). Cardiomyocytes (CM) were isolated at 6 weeks PP and ROS and peroxynitrite levels determined using fluorescent dyes. Results: In WT mice, all normal maternal CV adaptions to pregnancy, reverted to pre-pregnant levels 6 weeks PP. In contrast, GSNOR -/- mice exhibited increased cardiac output (+21% vs. -19% in WT), stroke volume (+21% vs. -41% in WT), and LV chamber dimension (+13% vs. -4% in WT) at 6 weeks PP, indicating high cardiac output LV cardiomyopathy. CM isolated from GSNOR -/- hearts showed ~5-fold more ROS generation (9.9x10 -4 ±9x10 -5 vs. 2.1x10 -4 ±1.5 x10 -4 ΔF/F max .min -1 ) and elevated peroxynitrite levels (0.318±0.011 vs. 0.243±0.012 ΔF/F 0 ) compared to WT at 6 weeks PP, suggesting the presence of nitroso-redox imbalance. All changes P<0.05. Conclusion: Postpartum GSNOR -/- (preeclamptic) mothers exhibited cardiac dysfunction which was accompanied by the presence of of nitroso-redox imbalance. These changes may predispose the mother to higher risk for future CV injury.