Peripartum stress deteriorates cardiac function in female mice with a cardiomyocyte-specific deletion of myosin-5b

Background & aim:

Peripartum cardiomyopathy (PPCM) is characterized by maternal systolic heart failure (HF) due to left ventricular (LV) dysfunction in heart-healthy women occurring between in the last month before, under delivery and in the months thereafter.

Unconventional class-5 myosin motor proteins ensure intracellular sorting and trafficking of different cargoes. Here, we investigated the regulation and role of myosin-5b during pregnancy and postpartum in the maternal heart.

Methods & results:

Physiological peripartum stress was associated with increased cardiac Myo5b expression in WT mice after 2 consecutive pregnancies and nursing periods compared with age-matched nulli-pari (NP) mice. In contrast, mice with PPCM due to cardiac STAT3 deficiency showed a reduced Myo5b mRNA expression compared with WT PP mice.

The role of cardiac MYO5b in the peripartum phase was analyzed in mice with a cardiomyocyte-specific knockout (KO) of MYO5b (KO: αMHC-Cre;Myo5b^flox/flox; WT: Myo5b^flox/flox). Female KO mice developed normally up to the age of 3 months (M) with LV function comparable with WT mice (female FS%: WT: 36±12, KO: 35±7). Indeed, KO females developed a reduced cardiac function (6M female FS%: WT 31±11, KO 22±10, p<0.05) associated with premature mortality.

After exposing KO females to pregnancy and nursing (mating at the age of 8-10 weeks) echocardiographic analysis revealed a decrease in LV function in KO PP mice, compared with age-matched KO NP females, already after the first pregnancy and nursing period (FS%: KO NP: 33±6, KO PP: 23±7, P<0.01), which continued to decrease after the second pregnancy and nursing period (FS%: KO NP: 22±10, KO PP: 9±4, P<0.01). The mortality increased relative to the number of pregnancies and advancing age (P<0.05), compared with age-matched KO NP females. Molecular and morphologic analysis after 2 consecutive pregnancy and nursing periods revealed that KO PP mice developed enhanced cardiac hypertrophy characterized by increased heart weight, cardiomyocyte cross-sectional area and an elevated mRNA expression of the hypertrophic and HF markers Anp, Bnp and Ankrd1 compared with KO NP mice. Moreover, KO PP mice displayed increased cardiac fibrosis (indicated by Sirius red staining and upregulated Col1a1 mRNA expression) and inflammation (upregulated Adgre1, Tnfa and Il-6 mRNA expression). Indeed, the PPCM biomarkers PAI-1 and miR-146a were increased and the cardioprotective ErbB4 signalling is reduced in LV tissue of KO PP compared with KO NP. Moreover, GLUT4 mRNA and protein expression were reduced in LV tissue of KO PP compared to KO NP. Further analyses in isolated adult cardiomyocytes revealed that MYO5b is involved in baseline and insulin induced cardiac glucose uptake and is associated to mitochondrial proteins.

Conclusion:

Myo5b is upregulated late in pregnancy and postpartum suggesting a potential role in the compensation of peripartum stress in the maternal heart. Impaired cardiac myosin-5b expression promotes HF in the peripartum phase. First data suggest that myosin-5b is involved in the cardiac metabolism.