# PGC-1α, Purines and the Postmenopausal Heart

> **NIH NIH R21** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $218,750

## Abstract

Cardiovascular disease (CVD) is the leading cause of death of women in the United States, accounting for
around 1 of every 3 deaths. Estrogen deficiency, as seen in aging women or after oophorectomy, has been
linked to loss of cardiovascular protection, typically seen during reproductive life. Up to half of women
evaluated for myocardial ischemia have normal appearing coronary arteries. These women can develop heart
failure with a preserved ejection fraction (termed HFpEF) for which the etiology is unclear. Hormonal
replacement therapy (HRT) after menopause remains controversial but current evidence cannot support this
for either primary or secondary prevention of CVD. There are clearly modulatory influences on estrogenic
signaling, that could well influence cardiovascular health in later life. Previous studies have demonstrated that
estrogen improves energy production within the heart by increasing 5' adenosine monophosphate-activated
protein (AMPK) and mitochondrial biogenesis via upregulation of peroxisome proliferator-activated receptor
gamma coactivator 1-alpha (PGC-1α); a master switch of mitochondrial function, linked to vascular integrity
and angiogenesis. Estrogen has been also found to modulate purinergic signaling by boosting expression of
adenosine receptors and of CD39, the dominant endothelial ecto-ADPase that generates adenosine. There are
also close relationships between purinergic signaling and dipeptidyl peptidase-4 (DPP-4; otherwise known as
adenosine deaminase complexing protein 2 or CD26), possibly mediated by adenosine deaminase bioactivity.
Decreased PGC-1α and aberrant purinergic signaling in metabolic syndrome may lead to impaired
mitochondrial function, provoking diastolic dysfunction, and also result in impaired angiogenesis. We
hypothesize there are central roles of PGC-1α, purines and DPP-4 linked neuropeptide pathways in the
control of angiogenesis and mitochondrial activity. These become increasingly disordered in setting of estrogen
loss provoking development of metabolic syndrome, thereby exacerbating HFpEF and microvascular disease.
Specific Aim 1: To determine how ischemia and cardiometabolic dysfunction in women's heart disease
are exacerbated by the loss of puringeric pathways from estrogen deficiency. We expect to determine
that diastolic dysfunction is a functional consequence of this microvascular loss and cardiometabolic
dessynchrony. Specific Aim 2: To evaluate the role of adenosingergic receptor activation and DPPIV
inhibition on angiogenesis in a ovariectomized swine model of chronic myocardial ischemia and
metabolic syndrome. Here, we will explore relationships between the regulated and linkages in the
exocytosis of nucleotides and neuropeptides, formation of nucleosides (adenosine) and alterations in
angiogenic activity secondary to these. Summary: We will study fundamental mechanisms in heart disease
underpinning biological differences in women. We will also offer new therapeutic strategies that targ...

## Key facts

- **NIH application ID:** 10127753
- **Project number:** 1R21AG065923-01A1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Robina Matyal
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $218,750
- **Award type:** 1
- **Project period:** 2021-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127753

## Citation

> US National Institutes of Health, RePORTER application 10127753, PGC-1α, Purines and the Postmenopausal Heart (1R21AG065923-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10127753. Licensed CC0.

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