Ebenebe-Kasonde, O. V. | Search bioRxiv

bioRxiv2025

Formate reduces ischemic injury in female hearts lacking alcohol dehydrogenase 5

Ischemic heart disease is a primary cause of death for men and women in the United States. Recent epidemiologic findings, however, suggest that pre-menopausal women have inherent protection from many cardiovascular pathologies compared to age-matched men, which is lost with menopause. We and others have documented similar protective signaling in animal models, with females exhibiting protection from ischemic injury that is lost with ovariectomy (OVX). Furthermore, in recent studies, we demonstrated that the loss of alcohol dehydrogenase 5 (ADH5) blocked sex-specific cardioprotection in females, but activation of aldehyde dehydrogenase 2 (ALDH2) provided a rescue. ADH5 and ALDH2 both metabolize formaldehyde to formate, potentially implicating formate in female-specific cardioprotection. Therefore, the objective of this study was to examine a role for formate during ischemic injury in female hearts using wild-type (WT) and ADH5-/- mice. We also aimed to explore estrogen-dependent effects by using ovariectomized (OVX) WT mice. To assess the protective effects of formate in intact female WT and ADH5-/- hearts, as well as OVX WT hearts, hearts were Langendorff-perfused and subjected to ischemia/reperfusion (I/R) injury. Since formate is used in one-carbon metabolism (OCM), select OCM enzymes were also probed via western blot. Importantly, we found that formate significantly reduced infarct size in female ADH5-/- hearts subjected to I/R injury, but formate was without effect in intact female WT hearts. Additionally, formate failed to reduce I/R injury in OVX WT hearts, despite OVX WT hearts exhibiting reduced ADH5 and ALDH2 activity. However, we noted that the expression of certain OCM enzymes was downregulated in OVX WT hearts vs. intact WT females, which may prevent proper formate utilization by OCM in OVX WT hearts. Furthermore, blockage of formate import into OCM in intact female WT hearts also exacerbated I/R injury. Taken together, our findings support formate utilization by OCM as a key component of cardioprotective signaling in female hearts, with estrogen acting as a potential mediator.

physiology↗

bioRxiv2024

Gestational arsenite exposure alters maternal postpartum heart size and induces Ca2+ handling dysregulation in cardiomyocytes

Cardiovascular disease is the leading cause of mortality in the US. Studies suggest a role for environmental exposures in the etiology of cardiovascular disease, including exposure to arsenic through drinking water. Arsenic exposure during pregnancy has been shown to have effects on offspring, but few studies have examined impacts on maternal cardiovascular health. While our prior work documented the detrimental effect of arsenic on the maternal heart during pregnancy, our current study examines the effect of gestational arsenic exposure on the maternal heart postpartum. Timed-pregnant wild-type (C57BL/6J) mice were exposed to 0, 100 or 1000 {micro}g/L sodium arsenite (NaAsO2) via drinking water from embryonic day 2.5 (E2.5) until parturition. Postpartum heart structure and function was assessed via transthoracic echocardiography and gravimetric measurement. Hypertrophic markers were probed via qRT-PCR and western blot. Isolated cardiomyocyte Ca2+-handling and contraction were also assessed, and expression of proteins associated with Ca2+ handling and contraction. Interestingly, we found that exposure to either 100 or 1000 {micro}g/L sodium arsenite increased postpartum heart size at P12 vs. non-exposed postpartum controls. At the cellular level, we found altered cardiomyocyte Ca2+-handling and contraction. We also found altered expression of key contractile proteins, including -Actin and cardiac myosin binding protein C (cMyBP-c). Together, these findings suggest that gestational arsenic exposure impacts the postpartum maternal heart, possibly inducing long-term cardiovascular changes. Furthermore, these findings highlight the importance of reducing arsenic exposure during pregnancy, and the need for more research on the impact of arsenic and other environmental exposures on maternal heart health and adverse pregnancy events. New & NoteworthyGestational exposure to sodium arsenite at environmentally relevant doses (100 and 1000 {micro}g/L) increases postpartum heart size, and induces dysregulated Ca2+ homeostasis and impaired shortening in isolated cardiomyocytes. This is the first study to demonstrate that gestational arsenic exposure impacts postpartum heart structure and function beyond the exposure period.

pharmacology and toxicology↗