Connecting sex differences, estrogen signaling, and microRNAs in cardiac fibrosis

Area of Science:

• Cardiovascular Biology
• Endocrinology
• Molecular Medicine

Background:

• Heart failure (HF) progression is exacerbated by cardiac fibrosis, a process lacking specific therapies.
• Cardiac fibroblasts (CFs) mediate fibrosis through phenotypic transition to myofibroblasts, originating from various cell types.
• Females exhibit less cardiac fibrosis than males, partly due to the protective effects of 17β-estradiol (E2).

Purpose of the Study:

• To review current knowledge on sex differences, E2, and estrogen receptors (ERs) in cardiac fibrosis.
• To emphasize the roles of microRNAs (miRNAs) and myofibroblast origins in sex-dimorphic cardiac fibrosis.
• To elucidate the multi-level regulatory networks involving sex, E2, and miRNAs in cardiac fibrosis.

Main Methods:

• Literature review of studies on sex differences in cardiac fibrosis.
• Analysis of E2 signaling pathways via estrogen receptors (ERs) in cardiac fibroblasts.
• Investigation of miRNA regulation by E2 in the context of cardiac fibrosis and myofibroblast transition.

Main Results:

• E2 and ERs significantly regulate cardiac fibroblast function and gene expression.
• E2 and ERs exhibit distinct effects on male and female cardiac fibrosis pathophysiology.
• Sex, E2, and miRNAs form complex regulatory networks influencing cardiac fibrosis, with sex-dimorphic and E2-regulated miRNAs impacting mesenchymal transition.

Conclusions:

• E2 and ERs are key regulators of cardiac fibroblast behavior and cardiac fibrosis, with important sex-specific implications.
• MicroRNAs play a crucial role in mediating the sex-dimorphic effects of E2 on cardiac fibrosis.
• Understanding these complex regulatory networks is essential for developing targeted therapies for cardiac fibrosis.