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 while 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 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 post-ischemic 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, post-ischemic levels of tetrahydrobiopterin (BH4), a cofactor necessary for NOS function, were preserved in formate-treated hearts. Collectively, our findings suggest that formate is a potent cardioprotective agent that preserves post-ischemic 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.