Does Senescence Impair the Cardiovascular Benefits of Menopause Hormone Therapy?

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Principal Investigator: Lin  Zhu
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $120,177
Funding agency: National Institute on Aging

Does Senescence Impair the Cardiovascular Benefits of Menopause Hormone Therapy?
 Atherosclerotic cardiovascular disease (ASCVD) causes approximately one-third of all deaths
worldwide. The protection in women against ASCVD is reduced with aging and menopause. Menopausal
hormone therapy (MHT) has not replicated this protection in postmenopausal women in clinical trials,
highlighting the gap in our knowledge of the mechanisms of the protecting roles of estrogens in young women
and impaired protection of MHT in aged women.
 The goal of this application is to investigate the mechanism by which MHT fails to reduce ASCVD
events despite metabolic improvements and to define a therapeutic approach to reduce ASCVD risk in aged
women. To recapitulate the physiology in postmenopausal women with MHT, mouse models of estradiol (E2)
treatment with surgical menopause and atherosclerosis regression have been designed. Preliminary studies
show that atherosclerosis burden under MHT was associated with blood inflammatory factor interferon
gamma (IFNg) levels when hyperlipidemia was reduced. These results mirror the clinical observation that
MHT could not improve postmenopausal ASCVD risk when the inflammation index is high. Aging and
senescence-related cellular dysfunction may drive inflammation in the artery wall even when the blood lipid
profile is normal. My overarching hypothesis is that inflammation resolution in atherosclerotic lesions is
impaired by senescence-related incompetence of arterial repair in postmenopausal women with MHT. I
propose that ASCVD risk will be reduced with MHT when lipid risks and inflammation in atherosclerotic lesions
are resolved. I will explore this hypothesis with two Specific Aims: 1) Test the hypothesis that MHT improves
lipid metabolism but does not resolve arterial senescence and atherosclerotic inflammation. 2) Test the
hypothesis that correcting senescence and limiting inflammation in atherosclerotic lesions will restore the
cardiovascular benefits of menopause E2 treatment. Studies proposed in this application will reveal critical
mechanisms underlying why MHT fails to reverse atherosclerosis and lead to therapeutic approaches to
reduce ASCVD risk in postmenopausal women.
 My career goal is to lead a research team focused on managing ASCVD risks. I have a strong
background in lipid research and in the atherosclerosis field. The proposed project will afford me new
expertise in 1) studying cellular senescence and immune cell functions in inflammation resolution in
atherosclerosis regression, 2) translational science to reduce ASCVD risk by developing therapeutic methods
to block inflammation in the artery wall. I have proposed a career development plan that integrates formal
didactic training with a diverse hands-on mentorship committee to further refine my skills, competences, and
leadership ability. It is anticipated that completion of the proposed project and training plan will place me in
an ideal position to receive a tenure track faculty position.

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