ASSESSING MENOPAUSAL FEMALE SUSCEPTIBILITY TO HEART DISEASE: A FOCUS ON AMPK’S ABILITY TO MITIGATE CARDIAC REMODELING THROUGH ESTROGEN-DEPENDENT GENE PROGRAMS

Abstract

Premenopausal women are protected against cardiovascular disease (CVD) compared to age-matched men. The cellular and molecular mechanisms underlying the transition from premenopause/perimenopause (CVD-resistance) to postmenopause (CVD-susceptible) in women is unknown and is the focus of this project. The critical barrier impeding translational progress is the lack of appropriate models to study menopause. Most studies have used surgical removal of ovaries as a model of menopause; yet this technique poorly recapitulates the natural, physiological transition to menopause that 90% of women experience. I have overcome this barrier with the VCD model of menopause, which mirrors progressive ovarian failure and preserves the critical ‘perimenopause’ transitional period. Our finding that perimenopausal females remain protected underscores the importance of studying the role of estrogen in CVD, across the transition from perimenopause to menopause. Multiple molecular, genetic, and cellular mechanisms underlie protection against CVD in non-cycling females, many of which put estrogen as the key mediator. We previously discovered that the AMP-activated kinase (AMPK) signaling axis is activated by estrogen through direct binding of estrogen receptors to the ?-catalytic subunit of AMPK. I aim to utilize the AMPK signaling pathway to determine if AMPK activation is necessary for prevention of CVD during menopause.