# Sex Differences in Endogenous Formaldehyde Production and One-Carbon Metabolism: Potential Links to Cardioprotection

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2022 · $46,752

## Abstract

PROJECT SUMMARY
Ischemic heart disease is a leading cause of death in the US, often manifesting as ischemia/reperfusion injury.
Premenopausal women are at lower risk for ischemic heart disease than age-matched men, but this protection
is lost following menopause, supporting a role for estrogen. In prior studies, we found that female hearts have
two-fold more formaldehyde compared to males and higher activities of the two enzymes that metabolize
formaldehyde to formate. Formaldehyde is a byproduct of one-carbon metabolism, and formate can be used in
subsequent one-carbon reactions. Therefore, it is possible that formate may be used in one-carbon metabolism
to drive cardioprotective signaling in the female heart, possibly by producing the protective molecules
tetrahydrobiopterin and glutathione, but additional research is required to define female-specific cardioprotection.
Tetrahydrobiopterin is a cofactor for nitric oxide synthase, a primary nitric oxide source which we have found to
be protective during ischemia/reperfusion injury. Additionally, one-carbon metabolism produces the antioxidant
glutathione, and females have been found to be more resistant to oxidative stress compared to males. Therefore,
I hypothesize that the female heart produces formaldehyde via one-carbon metabolism which is then
metabolized to formate for use in the one-carbon pathway to promote cardioprotective signaling via
tetrahydrobiopterin and glutathione production. This hypothesis will be tested in the following aims: 1) Identify
the role of estrogen in formaldehyde and formate production during ischemia/reperfusion injury, 2) Define the
link between formate and nitric oxide production in the heart during ischemia/reperfusion injury, and 3) Define
the link between formate and antioxidant capacity in the heart during ischemia/reperfusion injury. Upon
successful completion, this proposal will elucidate critical protective signaling pathways in the female heart,
which are largely unknown, and potentially unlock critical therapeutic insights for cardioprotection in men and
postmenopausal women.

## Key facts

- **NIH application ID:** 10536259
- **Project number:** 1F31HL165820-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Haley Caitlin Garbus
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-09-30 → 2025-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536259

## Citation

> US National Institutes of Health, RePORTER application 10536259, Sex Differences in Endogenous Formaldehyde Production and One-Carbon Metabolism: Potential Links to Cardioprotection (1F31HL165820-01). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/10536259. Licensed CC0.

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