MON-045 - TMT Mass Spectrometry Analysis of the Heart and the Brain Post Menopause

The depletion of circulating estradiol (E2) during menopause increases the risk of cardiovascular disease and dementias. To combat these health issues, hormone replacement therapy (HRT) was introduced. In 1990, the Women’s Health Initiative (WHI) conducted a clinical study of post-menopausal women receiving HRT, but the study was halted early due to a higher stroke incidence in women receiving HRT. This lead many to believe that HRT is not a suitable treatment for menopause. The "timing hypothesis" was posited as one explanation for these negative outcomes: HRT is beneficial when started at/close to the onset of menopause, but if there is a major delay before treatment (10 years between the onset of menopause and the start of HRT) then the risk of neurological and cardiovascular disease is exacerbated. However, we have an incomplete understanding of the molecular events driving this timing-dependent phenomenon. In this study, we used an unbiased proteomics approach (Tandem Mass Tag - TMT) to define the changing proteomic landscape of the heart and brain in a rat model of menopause. We ovariectomized 18-month-old Fisher344 rats and waited 1 or 4 weeks before treatment with E2 or a vehicle control to model early vs. late HRT. We then isolated tissue from the heart (left ventricle) and the brain (hypothalamus) and prepared samples for TMT mass spectrometry to quantify the proteomic changes due to age, E2 treatment or both. Our results demonstrated that extended E2 deprivation leads to distinct changes in the heart proteome, and in proteins relevant for heart disease. Moreover, we identified changes in proteins important for synaptic transmission and neuroendocrine functions of the hypothalamus. These global proteomic shifts could explain why the neuro- and cardioprotective effects of E2 fail to be preserved following extended periods of E2 deprivation.

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