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Formate Confers Sex-Specific Protection Against Myocardial Ischemia-Reperfusion Injury
Raihan Kabir
*1, Haley Garbus-Grant
2, Obialunanma Ebenebe-Kasonde
2, Nicole Taube
2, Deepthi Ashok
3, Brian O’Rourke
3, Mark J. Kohr
21University of Vermont Larner College of Medicine, Burlington, VT; 2Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; 3Johns Hopkins University School of Medicine, Baltimore, MD
Background. Formate (FM) is a one-carbon metabolite critically involved in redox balance and bioenergetics, yet its role in the heart remains unexplored. FM is generated in part by formaldehyde dehydrogenase (FDH), and previous work from our group demonstrates that the knockout or inhibition of FDH exacerbates ischemia-reperfusion (I/R) injury in the female mouse heart. Considering that FM depletion may be detrimental, we tested the hypothesis that FM yields cardioprotective benefit in myocardial I/R injury.
Study Design. Hearts from male and female wild type (WT) and FDH-/- mice (n=5-10/group) were subjected to global ex vivo I/R injury with or without FM via Langendorff perfusion.
Results. Knockout of FDH ablated endogenous sex-dependent cardioprotection in the female mouse heart, and administration of FM served as a rescue (p=0.0043). Interestingly, FM perfusion increased post-ischemic functional recovery in the WT male heart, quantified by percent pre-ischemic left ventricular rate-pressure product (p=0.0023), and decreased infarct size (p<0.0001). Exogenous FM did not elicit a significant phenotype in the WT female heart, potentially due to elevated endogenous plasma FM in female mice at baseline, suggesting that the mechanisms of FM-mediated cardioprotection may be saturated in the female myocardium. Neonatal rat ventricular myocytes subjected to I/R injury in vitro, independent of plasma gonadocorticoids, demonstrated decreased lactate dehydrogenase release (p=0.0196), indicating that FM confers a conserved, sex-modulated protective effect in the myocardium. Given the dual role of FDH in one-carbon metabolism and nitric oxide (NO) signaling, both mechanisms were probed. FM stimulated increases in a NO synthase cofactor and total protein S-NO, preserved post-ischemic protein S-NO, and suppressed post-ischemic oxidative stress, suggesting that FM maintains the nitroso-redox balance during I/R injury. Furthermore, FM increased mitochondrial protein expression, metabolic activity, and via mitochondrial stress test, enhanced the maximal respiratory capacity to respond to an increase in energetic demand (i.e., I/R).
Conclusion. FM mediates cardiac nitroso-redox homeostasis and mitochondrial bioenergetics to confer sex-specific protection against I/R injury in rodent myocardium. Taken together, these findings highlight one-carbon metabolism as a promising therapeutic target to manage ischemic heart disease and improve surgical outcomes.
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