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Glucocorticoid Receptor Signaling is Critical for microRNA Gender‐Specific Regulation of Gene Expression in the Adult Mouse Heart.

Heart disease remains a leading cause of death among women in the US. Stress is considered a risk factor for heart disease. Growing evidence indicates that women are more susceptible and present higher stress levels at baseline than men, suggesting an important role for stress signaling in female cardiac health. Glucocorticoids are the primary regulators of the stress response and exert their actions by binding the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily of transcription factors. GR has been shown to play a direct role in heart physiology, but its sexual dimorphic effects in cardiac gene expression are unclear. microRNAs regulate a plethora of cellular and physiological processes and dysregulation in their expression has been linked to heart disease. However, there are limited studies on gender‐specific differences in microRNAs expression and regulation in the adult heart. Our goal was to determine the contribution of GR signaling to the sexually dimorphic expression of microRNAs and their target genes in the mouse adult heart. To accomplish this objective, we performed a RNA‐seq and microRNA array on male and female hearts of the cardiomyocyte‐specific GR knockout (cardio GRKO) and their littermate controls (GR flox/flox). RNA‐seq data revealed that over 6000 genes are differentially expressed between male and female controls hearts at baseline. Data comparison between cardio GRKO and GR flox/flox showed that 3900 (65%) of the identified genes required GR for sexually dimorphic expression. In agreement with the RNA‐seq data, we found that 163 microRNAs were also influenced by sex and that GR was necessary for the gender‐specific regulation of 130 (~80%) of the identified microRNAs. Integrated analysis of microRNA and mRNA expression data revealed that 33 of the 163 identified sex‐dependent microRNAs target the expression of 4200 (70%) of the 6000 genes found differentially regulated in male and female control hearts. The expression of 25 of these 33 microRNAs depends on GR. Among the GR‐dependent microRNAs, we found miR 1–3p, miR‐29, miR‐128 and miR‐370, which are important biomarkers of heart failure in humans. Paired analysis of these 4 microRNAs and the RNA‐seq data, showed that 600 genes associated with cardiac hypertrophy, heart failure and hypoxia are targeted by these microRNAs. Among these genes, we found collagen type I alpha 1 (COL1A), epidermal growth factor receptor (EGFR), angiopoietin 2 (ANGPT2), myocardin (MYOCD) and endothelin receptor type B (EDNRB). These results suggest that GR regulation of microRNAs is a potential mechanism by which stress selectively modulates gene expression and consequently influences cardiac health in women.