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. 2019 Jul 17;8(15):e011012. doi: 10.1161/JAHA.118.011012

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© 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

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Pattern of gene expression between male and female hearts from control (glucocorticoid receptor [GR] fl/fl) and cardiomyocyte‐specific glucocorticoid receptor knockout mice. A, Heat map of RNA‐seq data with hierarchical clustering of genes that are differentially expressed between control and cardioGRKO male and female mice. Red indicates high‐expressing genes whereas blue indicates low‐expressing genes. B, Upper panel: Analysis of RNA‐seq results showing significantly altered genes in each comparison, male GRfl/fl to male cardioGRKO (4262 genes), female GRfl/fl to female cardioGRKO mice (4559 genes), male GRfl/fl to female GRfl/fl (6279 genes), and male cardioGRKO to female cardioGRKO (3879 genes). Lower panel: Venn diagram of the results overlaying male GRfl/fl vs female GRfl/fl (left circle) to male cardioGRKO vs female cardioGRKO mice (right circle). 2299 genes are in common between controls and cardioGRKO hearts (intersection). Cardiomyocyte GR regulates the expression 3980 sexually dimorphic genes in control hearts (64% of a total of 6279 genes are GR dependent). In the absence of GR, 1580 genes are differentially expressed between cardioGRKO male and female hearts. C, Upper right panel: Of the 4262 genes differentially expressed in male cardioGRKO hearts as compared with controls (GR fl/fl), 306 of these genes are directly or indirectly associated with GR. A similar number of GR associated genes, 392, were found among the 4559 genes with altered expression in the female cardioGRKO hearts. Comparison of these GR‐associated genes shows that ≈44% of these genes are unique to the cardioGRKO male hearts, while 56% are unique to the female knockout hearts. Upper left panel: Only 60 genes of the 4262 differentially expressed genes in the male cardioGRKO hearts have been related to mineralocorticoid receptor signaling, and only 89 genes of the total of 4559 female knockout dysregulated genes are associated to MR. Venn diagram of these genes overlaying male and female GRfl/fl vs cardioGRKO hearts shows that the majority (100% for males and ≈68% for females) of the reported MR‐associated genes are common between males and females. Lower panel: About 50% of the MR genes are commonly associated with GR. CardioGRKO indicates cardiomyocyte‐specific glucocorticoid receptor knockout; CGRkO, cardiomyocyte‐specific glucocorticoid receptor knockout; GR, glucocorticoid receptor.