Role of formaldehyde, formate and one-carbon metabolism in the female heart

甲醛、甲酸盐和一碳代谢在女性心脏中的作用

• 批准号: 10193514
• 负责人: Mark Jeffrey Kohr
• 金额: $ 20.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10193514
• 关键词: Address; Amino Acids; Anabolism; Antioxidants; Automobile Driving; Biology; Carbon; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cause of Death; Confocal Microscopy; DNA; Data; Endothelium; Enzymes; Epidemiology; Exhibits; Female; Fluorescent Probes; Folic Acid; Formaldehyde; Generations; Glycine Hydroxymethyltransferase; Goals; Gonadal Steroid Hormones; Healthcare; Heart; Histones; Human; In Vitro; Injury; Knowledge; Link; Mammals; Mass Spectrum Analysis; Menopause; Metabolic; Metabolism; Mitochondria; Monitor; Myocardial; Myocardial Ischemia; NOS3 gene; Nitric Oxide; Nitric Oxide Synthase; Ovariectomy; Oxides; Oxidoreductase; Pathology; Pathway interactions; Phenotype; Postmenopause; Pre-Clinical Model; Premenopause; Production; Protein Isoforms; Proteins; Purines; Reaction; Role; Serine; Source; Study models; Testing; Therapeutic; Thymine; United States; Woman; Work; adduct; aldehyde dehydrogenases; arm; cardioprotection; cytotoxic; cytotoxicity; demethylation; epidemiology study; in vivo Model; insight; ischemic injury; knock-down; male; men; metabolomics; novel; overexpression; oxidation; prevent; protective effect; source localization; targeted treatment; tetrahydrobiopterin

PROJECT SUMMARY Cardiovascular disease is the leading cause of death among men and women in the United States. Recent epidemiological findings support an intrinsic mechanism that protects pre-menopausal women from many cardiovascular pathologies and this protection is lost with menopause. Similar protective effects have been observed in preclinical models, suggesting that an understanding of the normal biology of the female heart could yield insight for effective cardiovascular therapeutics in humans. Recent work from our group demonstrates that free formaldehyde levels are two-fold higher at baseline in female hearts vs. males. Formaldehyde is a highly reactive electrophile produced as a byproduct of many cellular metabolic reactions and is known to induce cytotoxicity by forming adducts with DNA and protein. To counteract this cytotoxicity, formaldehyde dehydrogenase (FDH or GSNOR) and mitochondrial aldehyde dehydrogenase 2 (ALDH2) have evolved to oxidize formaldehyde to formate, which can act as a one-carbon source. One-carbon metabolism is essential for generating the building blocks required for amino acid, purine and thymine biosynthesis, but also for generating critical antioxidants and maintaining tetrahydrobiopterin (BH4), which is essential for nitric oxide synthase (NOS) function. Interestingly, female hearts exhibit increased FDH and ALDH2 activity vs. males, as well as higher endothelial NOS (eNOS) activity. Our preliminary findings show that FDH activity and formaldehyde levels decrease with ovariectomy (OVX) in female hearts, suggesting that endogenous formaldehyde is sex hormone- dependent. As such, the formaldehyde-formate arm of the one-carbon cycle may represent a resilient mechanism that benefits and protects female hearts by turning cytotoxic formaldehyde into formate to maintain BH4 levels and NOS activity, but this mechanism has not been examined in female hearts. Furthermore, we were the first to discover that the loss of FDH exacerbates ischemic injury in female hearts, resulting from a two-fold increase in post-ischemic formaldehyde, but ALDH2 activation rescued this injurious phenotype in female FDH-/- hearts. These results suggest that alterations to FDH activity and/or formaldehyde can drive myocardial pathology in females, but additional studies are needed to define a novel role for the formaldehyde-formate one- carbon arm in the biology of the female heart. This proposal will address this important knowledge gap in the following specific aims: 1) define the source and localization of endogenous formaldehyde generation in female hearts and 2) define a potential link between the formaldehyde-formate one-carbon arm and eNOS function in female hearts. If completed successfully, this study will advance our mechanistic understanding of the formaldehyde-formate one-carbon arm in the female heart and provide valuable insight into how this pathway may be targeted for the therapeutic treatment of cardiovascular disease.

项目概要 心血管疾病是美国男性和女性死亡的主要原因。最近的 流行病学研究结果支持保护绝经前妇女免受多种疾病侵害的内在机制 心血管疾病，这种保护作用会随着更年期而消失。类似的保护作用也曾出现过 在临床前模型中观察到的结果表明，了解女性心脏的正常生物学可以 为人类有效的心血管治疗提供见解。我们小组最近的工作表明 女性心脏的基线游离甲醛水平是男性心脏的两倍。甲醛是一种高度 反应性亲电子试剂是许多细胞代谢反应的副产物，已知会诱导 通过与DNA和蛋白质形成加合物而产生细胞毒性。为了抵消这种细胞毒性，甲醛 脱氢酶（FDH 或 GS​​NOR）和线粒体醛脱氢酶 2 (ALDH2) 已进化为 将甲醛氧化成甲酸盐，甲酸盐可以作为单碳源。一碳代谢对于 生成氨基酸、嘌呤和胸腺嘧啶生物合成所需的构建模块，还可以生成 重要的抗氧化剂和维持四氢生物蝶呤 (BH4)，这对于一氧化氮合酶 (NOS) 至关重要 功能。有趣的是，与男性相比，女性心脏表现出更高的 FDH 和 ALDH2 活性，以及​​更高的 内皮一氧化氮合酶 (eNOS) 活性。我们的初步研究结果表明 FDH 活性和甲醛水平 女性心脏中的卵巢切除术 (OVX) 会降低，表明内源性甲醛是性激素 依赖。因此，一碳循环的甲醛-甲酸酯臂可能代表了一种有弹性的 通过将细胞毒性甲醛转化为甲酸盐来维持女性心脏的健康和保护机制 BH4 水平和 NOS 活性有关，但这种机制尚未在女性心脏中得到检验。此外，我们还 第一个发现 FDH 的缺失会加剧女性心脏的缺血性损伤，这是由两倍的 缺血后甲醛增加，但 ALDH2 激活挽救了女性的这种有害表型 FDH-/- 心。这些结果表明 FDH 活性和/或甲醛的改变可以驱动心肌 女性的病理学，但需要更多的研究来确定甲醛-甲酸盐的新作用- 女性心脏生物学中的碳臂。该提案将解决这一重要的知识差距 具体目标如下： 1）明确女性内源性甲醛生成的来源和定位 心和 2) 定义了甲醛-甲酸酯一碳臂与 eNOS 功能之间的潜在联系 女性的心。如果成功完成，这项研究将增进我们对这一机制的理解。 甲醛-甲酸盐单碳臂在女性心脏中的作用，并为该途径如何发挥作用提供了宝贵的见解 可以作为治疗心血管疾病的靶标。