Sex Differences in the Adverse Electromechanical Remodeling of the Heart after Repeated Witness Stress in Adult Rats: Relationship with a Specific miRNA Signature

Objective: Sex disparities in the association between psychosocial stress and cardiovascular risk have been reported, yet the extent to which social stress impacts cardiovascular function in a sex-specific manner remains unclear. The objectives of this study were to investigate sex differences in the electromechanical remodeling of the heart of socially stressed rats, and to explore potential epigenetic mechanisms (cardiac microRNAs). Methods: Adult wild-type Groningen rats of both sexes vicariously experienced the social defeat bout between two males for nine consecutive days ("witness stress" (WS) paradigm) or were exposed to a control condition (n=8/sex/group). After repeated WS exposure, arrhythmic vulnerability was evaluated via beta-adrenergic stimulation with isoproterenol in conscious rats, while cardiac contractile properties were assessed via hemodynamic analyses under anesthesia. Cardiac tissue was collected to measure expression levels of several miRNAs (including miR-22 and miR-34a) and their molecular targets (e.g., SIRT1) involved in the regulation of cardiac electromechanical function. Results: An increased vulnerability to isoproterenol-induced arrhythmias was found in male, but not female, rats with a history of WS. Signs of contractile dysfunction were found in both sexes after WS, but to a greater extent in males. In addition, only male WS rats exhibited a significantly higher cardiac expression of miR-34a and miR-22, which were associated with a reduced expression of their common molecular target (SIRT-1). Conclusion: These findings suggest an epigenetic mechanism underlying the larger vulnerability to adverse cardiac electromechanical remodeling in socially stressed male rats, informing our understanding of the sex-specific impact of social stress on cardiac function.