Sex Differences in Endogenous Formaldehyde Production and One-Carbon Metabolism: Potential Links to Cardioprotection

项目总结 在美国，缺血性心脏病是主要的死亡原因，通常表现为缺血/再灌注损伤。 绝经前女性患缺血性心脏病的风险比年龄匹配的男性要低，但这种保护 在绝经后丢失，支持雌激素的作用。在之前的研究中，我们发现女性的心脏 比男性多两倍的甲醛，代谢的两种酶的活性更高 甲醛生成甲酸盐。甲醛是一碳代谢的副产品，甲酸盐可用于 随后的一碳反应。因此，甲酸盐有可能用于一碳代谢。 在女性心脏中驱动心脏保护信号，可能是通过产生保护分子 四氢生物蝶呤和谷胱甘肽，但需要额外的研究来确定女性特有的心脏保护。 四氢生物蝶呤是一氧化氮合酶的辅助因子，我们已经发现一氧化氮合酶是一种主要的一氧化氮来源 在缺血/再灌注损伤中起到保护作用。此外，一碳新陈代谢产生抗氧化剂 与男性相比，女性对氧化应激的抵抗力更强。因此， 我假设女性心脏通过一碳代谢产生甲醛，然后 代谢为甲酸，用于一碳途径，通过以下途径促进心脏保护信号 四氢生物蝶呤和谷胱甘肽生产。这一假设将在以下目标中得到检验：1)确定 雌激素在缺血/再灌注损伤中甲醛和甲酸盐产生中的作用，2)确定 在缺血/再灌流损伤中，甲酸盐和一氧化氮的产生之间的联系，以及3)确定 在缺血/再灌注损伤中，甲酸盐与心脏抗氧化能力之间的联系。vt.在.的基础上 这项研究成功完成后，将阐明女性心脏中关键的保护性信号通路， 这些在很大程度上是未知的，并有可能揭开男性和 绝经后的女性。

PROJECT SUMMARY Ischemic heart disease is a leading cause of death in the US, often manifesting as ischemia/reperfusion injury. Premenopausal women are at lower risk for ischemic heart disease than age-matched men, but this protection is lost following menopause, supporting a role for estrogen. In prior studies, we found that female hearts have two-fold more formaldehyde compared to males and higher activities of the two enzymes that metabolize formaldehyde to formate. Formaldehyde is a byproduct of one-carbon metabolism, and formate can be used in subsequent one-carbon reactions. Therefore, it is possible that formate may be used in one-carbon metabolism to drive cardioprotective signaling in the female heart, possibly by producing the protective molecules tetrahydrobiopterin and glutathione, but additional research is required to define female-specific cardioprotection. Tetrahydrobiopterin is a cofactor for nitric oxide synthase, a primary nitric oxide source which we have found to be protective during ischemia/reperfusion injury. Additionally, one-carbon metabolism produces the antioxidant glutathione, and females have been found to be more resistant to oxidative stress compared to males. Therefore, I hypothesize that the female heart produces formaldehyde via one-carbon metabolism which is then metabolized to formate for use in the one-carbon pathway to promote cardioprotective signaling via tetrahydrobiopterin and glutathione production. This hypothesis will be tested in the following aims: 1) Identify the role of estrogen in formaldehyde and formate production during ischemia/reperfusion injury, 2) Define the link between formate and nitric oxide production in the heart during ischemia/reperfusion injury, and 3) Define the link between formate and antioxidant capacity in the heart during ischemia/reperfusion injury. Upon successful completion, this proposal will elucidate critical protective signaling pathways in the female heart, which are largely unknown, and potentially unlock critical therapeutic insights for cardioprotection in men and postmenopausal women.