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

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Abstract

Sex differences are evident in the pathophysiology of heart failure (HF). Progression of HF is promoted by cardiac fibrosis and no fibrosis-specific therapies are currently available. The fibrotic response is mediated by cardiac fibroblasts (CFs), and a central event is their phenotypic transition to pro-fibrotic myofibroblasts. These myofibroblasts may arise from various cellular origins including resident CFs and epicardial and endothelial cells. Both female subjects in clinical studies and female animals in experimental studies generally present less cardiac fibrosis compared with males. This difference is at least partially considered attributable to the ovarian hormone 17β-estradiol (E2). E2 signals via estrogen receptors to regulate genes are involved in the fibrotic response and myofibroblast transition. Besides protein-coding genes, E2 also regulates transcription of microRNA that modulate cardiac fibrosis. Sex dimorphism, E2, and miRNAs form multi-level regulatory networks in the pathophysiology of cardiac fibrosis, and the mechanism of these networks is not yet fully deciphered. Therefore, this review is aimed at summarizing current knowledge on sex differences, E2, and estrogen receptors in cardiac fibrosis, emphasizing on microRNAs and myofibroblast origins.

Key messages

• E2 and ERs regulate cardiac fibroblast function.

• E2 and ERs may distinctly affect male and female cardiac fibrosis pathophysiology.

• Sex, E2, and miRNAs form multi-level regulatory networks in cardiac fibrosis.

• Sex-dimorphic and E2-regulated miRNAs affect mesenchymal transition.

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Funding

This work was supported by National Institutes of Health grant R01HL131182 (ME).

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  1. Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine at University of California, Los Angeles, BH-550 CHS, Los Angeles, CA, 90095-7115, USA

    Lejla Medzikovic, Laila Aryan & Mansoureh Eghbali

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  1. Lejla Medzikovic
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  2. Laila Aryan
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Medzikovic, L., Aryan, L. & Eghbali, M. Connecting sex differences, estrogen signaling, and microRNAs in cardiac fibrosis. J Mol Med 97, 1385–1398 (2019). https://doi.org/10.1007/s00109-019-01833-6

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