Abstract
Several studies have demonstrated estrogen’s cardioprotective abilities in decreasing the fibrotic response of cardiac fibroblasts (CFs). However, the majority of these studies are not sex-specific, and those at the cellular level utilize tissue culture plastic, a substrate with a much higher stiffness than physiological conditions. Understanding the intrinsic differences between male and female CFs under more physiologically “healthy” conditions will help to elucidate the divergences in their complex signaling networks. We aimed to do this by conducting a sex-disaggregated analysis of changes in cellular morphology and relative levels of profibrotic signaling proteins in CFs cultured on 8 kPa stiffness plates with and without 17 β-estradiol (E2). Cyclic immunofluorescent analysis indicated that there was a negligible change in cellular morphology due to sex and E2 treatment and that the differences between male and female CFs occur at a biochemical rather than structural level. Several proteins corresponding to profibrotic activity had various sex-specific responses with and without E2 treatment. Single-cell correlation analysis exhibited varied protein–protein interaction across experimental conditions. These findings demonstrate the need for further research into the dimorphisms of male and female CFs to develop better tailored sex-informed prevention and treatment interventions of cardiac fibrosis.
Highlights
The prevalence of heart failure (HF) continues to rise, currently afflicting over 6.2 millionAmericans in roughly equal proportions among men and women [1,2]
Single-cell correlation analysis exhibited varied protein–protein interaction across experimental conditions. These findings demonstrate the need for further research into the dimorphisms of male and female cardiac fibroblasts (CFs) to develop better tailored sex-informed prevention and treatment interventions of cardiac fibrosis
To fully understand the differences male and female CFs interact with and respond to changes in their mechanochemical in how male and female CFs interact with and respond to changes in their mechanochemenvironment during fibrosis progression, it is necessary to know if any morphological ical environment during fibrosis progression,“healthy”
Summary
The prevalence of heart failure (HF) continues to rise, currently afflicting over 6.2 millionAmericans in roughly equal proportions among men and women [1,2]. Premenopausal women have a relative protection against HF compared to age-matched men which subsides after menopause [2,6]. This phenomenon has been studied extensively and is largely thought to be because of the ovarian hormone estrogen [3,4,7]. Following randomized clinical studies, HRT was shown to have overall adverse trends, increasing the risk of stroke, breast cancer, and heart attack in postmenopausal women, and is not recommended for long-term use or as a preventive measure for cardiovascular diseases [6,8]
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