Abstract Body: Background: While biological sex is widely recognized as a variable when it comes to myocardial injury and heart failure, little is known about the molecular mechanisms underlying these differences. Following a myocardial infarction (MI) the heart undergoes extensive extracellular remodeling that is in part driven by activated cardiac fibroblasts. The impact of biological sex on fibroblast activation and the importance of this difference in the remodeling heart is largely unknow.

Goal: To identify novel differences between male and female cardiac fibroblast populations.

Methods and Results: Cardiac fibroblasts were isolated from male and female mice and grown in culture. Cells were treated with either basic fibroblast growth factor (bFGF; control) or transforming growth factor beta (TGFb; activated) for 48 hours. Bulk RNA sequencing was used to identify changes in gene expression between male and female (n=4/group) cardiac fibroblasts in control or activated conditions. Female cardiac fibroblasts had increased expression of genes related to collagen compared to control males: Col1a1, Col1a2, Col3a1, Col5a1, and Col5a3 were all increased (Log2FC>0, q<0.05). Similarly, Col1a1, Col1a2, Col6a3, and Col8a2 were increased in TGF-activated female fibroblasts compared to TGF-activated male fibroblasts, indicating persistent differences in collagen expression (Log2FC>0, q<0.05). Genes related to cell cycling and division (Cdc6, Ube2c, Tk1, Eme1, Exo1, Pclaf, and Spc25) were decreased in activated female fibroblasts compared to activated male fibroblasts (Log2FC<0, q<0.05) indicating a potential difference in cell division and expansion.

Conclusion: Female cardiac fibroblasts have significant changes in gene expression related to collagen synthesis and cell division. These changes suggest that female cardiac fibroblasts produce more collagen, which could have important implications in scar formation and cardiac function. Additionally, a potential reduction in proliferation of activated female cardiac fibroblasts could have important implications for wound healing.