부산대학교 도서관

Introduction: Adverse childhood experiences, particularly early life stress (ELS), are associated with cardiovascular disease later in life but the underlying mechanisms remain elusive. Parental life experiences can have effects that are transmitted to the offspring suggesting a possible trans-generational transmission of ELS phenotypic traits.Hypothesis: ELS can impair cardiac function in exposed parents and their offspring.Methods: We used an ELS mouse model based on unpredictable separation of mouse pups (F1) from their mother (F0) each day for 3 hours from postnatal day 1 (PND1) to PND14 combined with dams exposure to an additional unpredictable stressor (forced swim in 18°C water for 5 minutes or 20-minute physical restraint in a tube) during separation. Control litters were raised normally. Echocardiography (Vevo 3100, Visualsonics) was performed at 6, 12 and 18 months in exposed animals (F0), their unexposed offspring (F1) and grand-offspring (F2). Both male and female mice were studied. Heart weight/tibia length was used to assess cardiac mass while Massonʼs Trichrome was employed to detect fibrosis. Lung congestion was assessed as lung wet/dry weight ratio. Single-cell RNA sequencing (scRNAseq) was performed in MSUS and control hearts. A 6-week environmental enrichment (EE) program (cages containing running wheels, maze) was employed to test the possible rescue of ELS effects in adult males and their offspring.Results: Male and female MSUS mice (F1) displayed a time-dependent deterioration (from 6 to 18 months) of LV hypertrophy, diastolic function, myocardial fibrosis and lung congestion when compared to controls. ScRNAseq revealed dysregulation of genes controlling inflammation and metabolism (Cav1, Fabp4) in cardiomyocyte and endothelial cell clusters. MSUS F1 and F2 females and males had diastolic dysfunction and lung congestion at 12 and 18 months (no change at 6 months). Notably, EE improved diastolic function and lung congestion in MSUS mice.Conclusions: ELS induces heritable cardiac alterations which can be rescued by EE in fathers. These results shed light on the causal role of ELS on heart failure development and potential mitigation strategies.