Supplemental Figures for "Myocardial transcriptomic and proteomic landscapes across the menopausal continuum in a murine model of chemically-induced accelerated ovarian failure"

Risk of cardiovascular disease (CVD) in women increases with the menopausal transition. Using a chemical model (4-vinylcyclohexene diepoxide; VCD) of accelerated ovarian failure, we previously demonstrated that menopausal females are more susceptible to CVD compared to peri- or pre-menopausal females like humans. Yet, the cellular and molecular mechanisms underlying this shift in CVD susceptibility across the pre- to peri- to menopause continuum remain understudied. In this work utilizing the VCD mouse model, we phenotyped cellular and molecular signatures from hearts at each hormonally distinct stage that included transcriptomic, proteomic and cell biological analyses. The transcriptional profile of pre-menopausal hearts clustered separately from peri-menopausal and menopausal hearts, which clustered more similarly. Proteomics also revealed hormonal clustering; peri-menopausal hearts grouped more closely with pre-menopausal than menopausal hearts. Both proteomes and transcriptomes showed similar trends in genes associated with atherothrombosis, contractility, and impaired nuclear signaling between pre-, peri-, and menopausal murine hearts. Further analysis of post-translational modifications showed hormone-dependent shifts in the phosphoproteome and acetylome. To further interrogate these findings, we triggered pathological remodeling using angiotensin II (Ang II). Phosphorylation of AMP-activated protein kinase (AMPK) signaling and histone deacetylase (HDAC) activity were found to be dependent on hormonal status and Ang II stimulation. Finally, knock-down of anti-inflammatory regulatory T cells (Treg) exacerbated Ang II-dependent fibrosis implicating HDAC-mediated epigenetic suppression of Treg activity. Taken together, we demonstrated unique cellular and molecular profiles underlying the cardiac phenotype of pre-, peri-, and menopausal mice supporting the necessity to study CVD in females across the hormonal transition.

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