AMP-Activated Protein Kinase (AMPK) and Estrogen-Dependent Mechanisms Underlying Increased Susceptibility to Cardiovascular Disease During Menopause
AdvisorKonhilas, John P.
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PublisherThe University of Arizona.
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AbstractIntroduction: More women than men have died from heart disease over the last 20-25 years. Menopausal women are prone to heart disease, and this is thought to be due to the loss of estrogen cycling. Current literature lacks an understanding of the cellular and molecular mechanisms that capture this transition from pre- to peri-menopause to menopause and the increased risk for cardiovascular disease (CVD). The 4-vinylcyclohexene diepoxide (VCD) model of menopause is a promising model to both assess epigenetic signaling in the menopausal heart and determine whether AMPK activation is sufficient for mitigation of pathological cardiac remodeling. We hypothesize that loss of energetic efficiency with the transition from pre- to menopause results in increased susceptibility to CVD and that cardioprotection will be restored in peri- and menopausal mice with AMPK activation. Methods: Utilizing the VCD model of menopause, pre-, peri-, and menopausal animals were monitored and treated with either saline, A769662 (AMPK direct activator), or hypertensive agent Angiotensin II (Ang II). Saline treated pre-, peri-, and menopausal mice were subjected to unbiased proteomics and transcriptomics, and these data were analyzed. Additionally, pre-, peri-, and menopausal mice underwent both short-term and long-term treatments with the activator and were assessed for changes in blood pressure, cardiac function, and fibrosis to determine the presence or absence of pathological cardiac remodeling. Results: The proteome and transcriptome analyses revealed unique and similar profiles for pre-, peri-, and menopausal mice, which implicated atherothrombosis, impaired contractility and impaired nuclear signaling. A769662 activator treatment was not a successful therapeutic agent across groups that were in menopause with and without Ang II-mediated hypertension and hypertrophic cardiac remodeling. Discussion: Our group is the first to show that A769662 treatment mitigates pathological cardiac remodeling during perimenopause with Ang II pathological stimulus. Phospho- and acetyl- modifications in contractile proteins detailed unique changes in pre-, peri-, and menopausal mice indicative of hypertrophy and fibrosis with the loss of estrogen. Additionally, we were also able to identify regulation of histone deacetylases (HDACs) as an alternative therapy for mitigating heart disease in menopausal females.
Degree ProgramGraduate College