Abstract 12075: S-nitrosoglutathione Reductase (GSNOR) Plays an Essential Role In Vasodilation, Maternal Cardiovascular and Renal Adaptation and Fetal Outcome in Pregnant Mice
Introduction: Preeclampsia is associated with elevated levels of S-nitrosylated proteins, abnormal cardiovascular and renal adaptations and poor fetal outcome. Mice lacking S-nitrosoglutathione reductase (GSNOR), a denitrosylase that regulates S-nitrosylation, show increased levels of S-nitrosylated proteins, have smaller litters and produce pups that exhibit perinatal growth-restriction. We hypothesized that poor fetal outcome in GSNOR-/- mice was due in part to maternal hypertension and abnormal cardiovascular and renal adaptation to pregnancy.
Methods: Pregnant GSNOR-/- (n=6) and control (C57Bl/6J) mice (n=6) were studied. Proteinuria was determined (E14.5) using dipstick, blood pressure was determined using a Millar catheter, and LV chamber dimensions and wall thicknesses were measured using echo at E17.5.
Results: The normal physiological increases in maternal cardiac output (Fig 1, P<0.001) and LV end-diastolic dimensions (P<0.01) seen during pregnancy were completely abrogated in GSNOR-/- mice at E17.5. Whereas, GSNOR-/- mice showed proteinuria at E14.5, and glomerulosclerosis and hypertension (105±3 mmHg vs. 90±2 mmHg in controls, P<0.001) at E17.5. In addition, the anterior wall was thicker (19%, P<0.01), contributing to higher relative wall thicknesses (37%, P<0.01) in GSNOR-/- mice. Furthermore, cardiomyocyte width (18%, P<0.05) was greater in GSNOR-/- mice, likely contributing to their hearts being larger (10%, P<0.01) at E17.5. The kidneys of pregnant GSNOR-/- mice were heavier (18%, P<0.05) and glomerular size was greater (42%, P<0.05) as compared to controls.
Conclusion: These results suggest that the tight regulation of S-nitrosylation by GSNOR during pregnancy promotes favorable fetal outcome by promoting enhanced maternal cardiovascular and renal adaptation. These findings highlight the crucial physiological role of denitrosylation in the pathophysiology of preeclampsia.
- © 2012 by American Heart Association, Inc.