Formaldehyde dehydrogenase-derived formate contributes to cardioprotection in the female heart

Ischemic heart disease (IHD) is a leading cause of death for men and women in the US, often manifesting as myocardial ischemia/reperfusion (I/R) injury. The risk for IHD, however, is considerably lower in premenopausal women vs. age-matched men and postmenopausal women, suggesting an estrogen (E2)-dependent protective mechanism. Previously, we found female hearts to contain two-fold more formaldehyde (FA) vs. males, but also higher activity of FA dehydrogenase (FDH), which detoxifies FA to formate. Importantly, we found that FDH inhibition or knockout exacerbates I/R injury in female hearts, potentially due to a lack of FDH-derived formate, yet mechanistic data is lacking. The objective of this study is to investigate a potential role for E2 in the regulation of FA production and FDH-mediated metabolism of FA to formate. We also aim to understand the link between FA metabolism and protection in female hearts. We hypothesize that E2 enhances FA metabolism in female hearts to increase formate production and contribute to protection from I/R injury. Our findings show a significant decrease in FDH activity in ovariectomized (OVX) female hearts, but also decreased FA vs. intact females, suggesting that FA production and metabolism are E2-dependent. To determine differences in enzymes for FA production, western blots were performed in lysates from male, female, and OVX mouse hearts. Serine hydroxymethyltranserfases 1 and 2 were more highly expressed in females vs. males. Lysine-specific demethylase 1 expression was significantly higher in female hearts vs. OVX and males. To further assess a role for formate in I/R injury, male and female hearts were Langendorff-perfused in the presence or absence of 30 μM formate. While formate treatment reduced infarct size in both sexes, this effect was more pronounced and significant in males (male: 36.6 +/- 5.45% vs. 10.3 +/- 1.46%, n = 9-10, p < 0.001; female: 19.9 +/- 1.57% vs. 15.8 +/- 1.70%, n = 9-10, p = 0.11). We also found more formate in plasma from females vs. males potentially explaining the blunted protection observed with formate in females. More importantly, we found that formate served as an effective rescue for FDH knockout female hearts, significantly reducing infarct size following I/R injury (60.0 +/- 3.55% vs. 40.2 +/- 2.79%, n = 6, p < 0.01). Taken together, our findings demonstrate that formate protects against I/R injury and further suggest that FDH-derived formate is a critical component of female-specific cardioprotection. As FDH is essential for female-specific cardioprotection from I/R injury, we will next determine whether formate rescues OVX hearts to determine its therapeutic potential for postmenopausal women. NHLBI 5T32ES007141 (HG), AHA 903435 (HG), NHLBI 1F31HL165920-01 (HG), RO1HL13649 (MK) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.