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

项目摘要 缺血性心脏病是美国的主要死亡原因，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低于年龄匹配的男性，但这种保护 在绝经后消失，支持雌激素的作用。在之前的研究中，我们发现女性的心脏 与男性相比，甲醛的含量是男性的两倍，两种代谢酶的活性也更高。 甲醛转化为甲酸盐。甲醛是一碳代谢的副产物，甲酸盐可用于 随后的一碳反应。因此，甲酸盐可能用于一碳代谢 来驱动女性心脏中的心脏保护信号，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异性心脏保护。 四氢生物蝶呤是一氧化氮合酶的辅因子，一氧化氮合酶是一氧化氮的主要来源，我们发现它 在缺血/再灌注损伤期间具有保护作用。此外，一碳代谢产生的抗氧化剂 已经发现，与男性相比，女性对氧化应激的抵抗力更强。因此，我们认为， 我假设女性的心脏通过一碳代谢产生甲醛， 代谢为甲酸盐，用于一碳途径，以通过 四氢生物蝶呤和谷胱甘肽产生。这一假设将在以下目标中进行检验：1）识别 雌激素在缺血/再灌注损伤过程中甲醛和甲酸产生中的作用，2）定义 缺血/再灌注损伤期间心脏中甲酸盐和一氧化氮产生之间的联系，以及3）定义 缺血/再灌注损伤期间心脏中甲酸盐和抗氧化能力之间的联系。后 成功完成后，该提案将阐明女性心脏中的关键保护信号通路， 这在很大程度上是未知的，并可能揭示关键的治疗见解，为心脏保护的男性， 绝经后妇女。

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.