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

内源性甲醛产生和一碳代谢的性别差异：与心脏保护的潜在联系

基本信息

批准号：
10894590
负责人：
Haley Caitlin Garbus
金额：
$ 4.77万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2025-09-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10894590
关键词：
Accounting Address Age Antioxidants Attenuated Biochemical Pathway Biological Assay Biological Availability Carbon Cardiac Cause of Death Enzymes Estrogens Exhibits Female Formaldehyde Formates Generations Genetic Glutathione Heart Heart Diseases In Vitro Ischemia Knowledge Link Lysine Mediating Metabolism Methods Methylenetetrahydrofolate reductase (NADPH)Methyltransferase Myocardial Ischemia Nitric Oxide Nitric Oxide Synthase Outcome Ovariectomy Oxidative Stress Oxidoreductase Pathway interactions Perfusion Population Postmenopause Pre-Clinical Model Premenopause Process Production Reaction Reperfusion Injury Reporting Research Resistance Risk Role Serine Sex Differences Signal Pathway Signal Transduction Source Testing Therapeutic United States Woman Work aldehyde dehydrogenases cardioprotection cofactor enzyme activity in vivo insight ischemic injury male men novel oxidative damage pharmacologic sex tetrahydrobiopterin

项目摘要

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.

项目概要缺血性心脏病是美国的一个主要原因，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同龄男性，但这种保护绝经后丢失，支持雌激素的作用。在之前的研究中，我们发现女性的心脏有与男性相比，甲醛含量高出两倍，并且两种代谢酶的活性更高甲醛转化为甲酸盐。甲醛是一碳代谢的副产物，甲酸可用于随后的一碳反应。因此，甲酸有可能用于一碳代谢可能通过产生保护性分子来驱动女性心脏的心脏保护信号传导四氢生物蝶呤和谷胱甘肽，但需要进一步的研究来定义女性特异性的心脏保护作用。四氢生物蝶呤是一氧化氮合酶的辅助因子，一氧化氮合酶是我们发现的主要一氧化氮来源在缺血/再灌注损伤期间起保护作用。此外，一碳代谢产生抗氧化剂谷胱甘肽，并且发现女性比男性更能抵抗氧化应激。所以，我假设女性心脏通过一碳代谢产生甲醛，然后代谢为甲酸盐，用于一碳途径，通过以下方式促进心脏保护信号传导：四氢生物蝶呤和谷胱甘肽的生产。该假设将在以下目标中进行检验：1）识别雌激素在缺血/再灌注损伤期间甲醛和甲酸盐生成中的作用，2) 定义缺血/再灌注损伤期间心脏中甲酸盐和一氧化氮生成之间的联系，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。之上如果成功完成，该提案将阐明女性心脏中关键的保护信号通路，这些在很大程度上是未知的，但有可能解锁男性和女性心脏保护的关键治疗见解绝经后妇女。