Abstract Body: Introduction: Preeclampsia (PE), a leading cause of maternal mortality, is linked to cardiac hypertrophy and impaired relaxation, predisposing the mother to an increased risk of cardiovascular (CV) injury during pregnancy. Mice lacking S-nitrosoglutathione reductase (GSNOR^–/– mice) exhibit all the clinical features of PE. Calcium regulation plays an important role in cardiac relaxation and hypertrophy, but whether alterations in calcium handling contribute to the impairment in these PE mice is unknown.
Hypothesis: Cardiac hypertrophy and impaired relaxation in pregnant GSNOR^–/– mice may be due in part to altered Ca²⁺ handling mechanisms.
Methods: Pregnant control (WT [C57B6]) and GSNOR^–/– mice were examined at non-pregnant (NP) and late pregnancy (17.5 dpc). Cardiomyocytes (CMs) were isolated (N=3-4 mice/group; n=8-24 CMs/heart) and assessed for intracellular Ca²⁺ and sarcomere shortening using IonOptix. Ca²⁺ decay and sarcomere relaxation rates were recorded. Ventricular tissue homogenates were assessed for Ca²⁺ handling and sarcomere-associated protein expression and post-translational modifications by Western Blot.
Results: At late pregnancy, the CMs of GSNOR^–/– mothers were significantly wider and systolic and diastolic Ca²⁺ levels were elevated as compared to WT. At 17.5 dpc, expression of Ca²⁺ handling proteins, RyR2, L-TCC and NCX1 were increased, and phosphorylation of RyR2 and L-TCC were increased in the GSNOR^–/– mothers as compared to WT. The Ca²⁺ decay rate improved in CMs from pregnant versus NP WT CMs but not in GSNOR^–/– CMs. PLB phosphorylation at Thr-17 was augmented in pregnant WT hearts, while phosphorylation at Ser-16 was reduced in pregnant GSNOR^–/–. Sarcomere relaxation parameters and sarcomere resting length were improved in CMs from pregnant WT mice but were impaired in pregnant versus NP GSNOR^–/– mice in association with increased expression of MyBPC in pregnant GSNOR^–/–.
Conclusion: The PE-related cardiac hypertrophy and impaired relaxation at late pregnancy in GSNOR^–/– mice were associated with elevated cytosolic Ca²⁺ levels, altered expression and post-translational modifications of Ca²⁺ handling and sarcomeric proteins, which may predispose these mice to higher CV injury during pregnancy.