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.

项目摘要 心血管疾病是美国男性和女性死亡的主要原因。最近 流行病学研究结果支持一种内在机制，保护绝经前妇女免受许多疾病的侵袭。 心血管疾病，这种保护随着绝经而丧失。类似的保护作用 在临床前模型中观察到，这表明对女性心脏正常生物学的理解可以 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， 女性心脏的游离甲醛水平在基线时比男性高两倍。甲醛是一种高度 作为许多细胞代谢反应的副产物产生的反应性亲电体，已知其诱导 细胞毒性通过与DNA和蛋白质形成加合物而产生。为了抵消这种细胞毒性，甲醛 脱氢酶（FDH或GSNOR）和线粒体醛脱氢酶2（ALDH 2）已经进化为 将甲醛氧化成甲酸盐，甲酸盐可以作为一个碳源。一碳代谢对于 产生氨基酸、嘌呤和胸腺嘧啶生物合成所需的结构单元， 关键的抗氧化剂和维持四氢生物蝶呤（BH 4），这是必要的一氧化氮合酶（NOS） 功能有趣的是，与男性相比，女性心脏表现出增加的FDH和ALDH 2活性，以及更高的FDH和ALDH 2活性。 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 在女性心脏中，随着卵巢切除术（OVX）的减少，表明内源性甲醛是性激素- 依赖。因此，一碳循环的甲酸脱甲酸臂可以代表一种弹性的碳循环。 一种有益于和保护女性心脏的机制，通过将细胞毒性甲醛转化为甲酸盐， BH 4水平和NOS活性，但这一机制尚未在女性心脏中进行研究。此外，我们 第一个发现FDH的丧失加剧了女性心脏的缺血性损伤，这是由两个因素引起的。 缺血后甲醛增加，但ALDH 2激活挽救了女性中的这种损伤表型 FDH-/-心脏。这些结果表明，FDH活性和/或甲醛的改变可以驱动心肌细胞凋亡。 病理学在女性，但需要额外的研究，以确定一个新的作用，甲酸甲酯的一个- 女性心脏生物学中的碳臂。本提案将填补这一重要的知识空白， 具体目的如下：1）明确女性内源性甲醛的来源和定位 2）确定了在脱甲酸的一碳臂和eNOS功能之间的潜在联系， 女人的心如果成功完成，这项研究将促进我们对 在女性心脏中，甲酸脱甲酸一碳臂，并提供有价值的见解，了解这一途径如何 可以靶向用于心血管疾病的治疗性治疗。