Formate reduces cardiac ischemia-reperfusion injury in murine ex vivo and in vitro models

Ischemic heart disease is a leading cause of death in the United States. We and others have demonstrated that nitric oxide (NO) signaling and associated protein S-nitrosation (SNO) play a key role in reducing ischemic injury in the heart. We also find that although females typically exhibit endogenous protection from ischemic injury, this protection is abrogated with the loss of the formate-generating enzyme alcohol dehydrogenase 5 (ADH5), but formate supplementation provided a rescue. Here, we investigate the cardioprotective efficacy of formate in male hearts. Hearts were Langendorff-perfused and subjected to ischemia-reperfusion (IR) injury with and without formate. Formate-mediated protection was also examined using an in vitro model of coverslip-induced ischemic injury to identify cardiomyocyte-specific effects. We found that formate increases postischemic protein SNO levels and yields protection from IR injury in both ex vivo and in vitro models. However, NO synthase inhibition blocked the formate-mediated increase in protein SNO in vitro and attenuated protection from IR injury ex vivo. Furthermore, postischemic levels of tetrahydrobiopterin (BH₄), a cofactor necessary for NO synthase (NOS) function, were preserved in formate-treated hearts. Collectively, our findings suggest that formate is a potent cardioprotective agent that preserves postischemic BH₄ levels and enhances protein SNO levels through a NOS-dependent mechanism. These findings have significant implications for the clinical prevention and treatment of ischemic heart disease in males.NEW & NOTEWORTHY Formate perfusion before ischemia improved functional recovery and dramatically reduced infarct size following ischemia-reperfusion injury in male hearts. Mechanistically, formate-mediated protection was associated with preserved postischemic tetrahydrobiopterin levels and increased protein S-nitrosation levels. These findings represent an important step toward the treatment of ischemic heart disease in males.