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Formate Reduces Ischemic Injury in Female Hearts Lacking Alcohol Dehydrogenase 5
Haley Garbus-Grant1, Obialunanma V Ebenebe-Kasonde1, Raihan Kabir1
1Department of Environmental Health and Engineering Johns Hopkins Bloomberg School of Public Health Baltimore Maryland USA.
FASEB Bioadvances
|December 15, 2025
Summary
Formate utilization by one-carbon metabolism (OCM) is crucial for cardioprotection in female hearts, particularly when alcohol dehydrogenase 5 (ADH5) is deficient. Estrogen appears to mediate this protective effect against ischemic injury.
Area of Science:
- Cardiovascular Biology
- Metabolic Biochemistry
- Sex Differences in Disease
Background:
- Ischemic heart disease is a leading cause of death, with women experiencing distinct protective mechanisms lost post-menopause.
- Alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 2 (ALDH2) metabolize formaldehyde to formate, suggesting formate's role in female cardioprotection.
- Ovariectomy (OVX) in females mimics menopause, leading to loss of protection against ischemic injury.
Purpose of the Study:
- To investigate the role of formate in protecting female hearts from ischemia/reperfusion (I/R) injury.
- To explore estrogen-dependent effects on formate-mediated cardioprotection.
- To examine the involvement of one-carbon metabolism (OCM) enzymes in this process.
Main Methods:
- Langendorff-perfused hearts from wild-type (WT) and ADH5 knockout (ADH5-/-) female mice, including OVX WT mice, were subjected to I/R injury.
- Formate was administered to assess its effect on infarct size.
- Western blotting was used to analyze the expression of OCM enzymes.
Main Results:
- Formate significantly reduced infarct size in intact ADH5-/- female hearts but not in intact WT female hearts.
- Formate did not protect OVX WT female hearts from I/R injury, despite reduced ADH5 and ALDH2 activity.
- OCM enzyme expression was downregulated in OVX WT female hearts, and blocking formate import into OCM exacerbated I/R injury in intact WT hearts.
Conclusions:
- Formate utilization via OCM is a key component of cardioprotective signaling in female hearts.
- Estrogen likely mediates this cardioprotection, influencing OCM enzyme expression and formate utilization.
- Understanding this pathway could lead to novel therapeutic strategies for ischemic heart disease in women.
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