Metabolic Imaging of the Cardioprotective Effects of Alcohol and ALDH2 Activators

酒精和 ALDH2 激活剂的心脏保护作用的代谢成像

• 批准号: 8206864
• 负责人: Daniel M Spielman
• 金额: $ 47.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206864
• 关键词: Acids; Alanine; Alcohol consumption; Aldehydes; Animal Model; Animals; Appearance; Basic Science; Bicarbonates; Bolus Infusion; Cardiac; Cardiotonic Agents; Chest; Clinic; Clinical; Coenzymes; Complex; Critical Pathways; Development; Diagnostic; Diagnostic tests; Discipline; Drug Metabolic Detoxication; Engineering; Enzymes; Epidemiology; Ethanol; Event; Goals; Heart; Human; Image; Imaging technology; Injection of therapeutic agent; Injury; Ischemia; Isoenzymes; Laboratories; Liver; Longitudinal Studies; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Monitor; Myocardial; Myocardial Ischemia; NADH; Nicotinamide adenine dinucleotide; Oxidative Stress; Oxidoreductase; Patients; Physicians; Play; Protein Kinase C; Pyruvate; Pyruvate Metabolism Pathway; Rattus; Reperfusion Injury; Reperfusion Therapy; Research; Rodent; Rodent Model; Role; Signal Transduction; Slice; Spectrum Analysis; Technology; Therapeutic Agents; Time; Tissues; Translating; Translations; Validation; Work; alcohol effect; aldehyde dehydrogenases; base; computerized data processing; heart metabolism; in vivo; inhibitor/antagonist; insight; magnetic resonance spectroscopic imaging; multidisciplinary; novel; novel therapeutics; preconditioning; prevent; protective effect; public health relevance; pyruvate dehydrogenase; research study; response; tool

DESCRIPTION (provided by applicant): Whereas the cardioprotective effects of moderate ethanol consumption are documented in human epidemiological and animal experimental studies, excess ethanol consumption can cause cardiac damage, liver damage, and cancer. The underlying cellular and molecular mechanisms leading to ethanol-induced cardioprotection and ethanol-induced tissue damage are complex and not fully understood. In our work, we have demonstrated that an important aspect of the protective effects of ethanol proceeds through a direct preconditioning-like mechanism ultimately activating aldehyde dehydrogenase (ALDH2), the major mitochondrial enzyme for removing toxic aldehydes arising from oxidative stress. The recent advent of hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) provides unprecedented opportunities for real-time imaging of in vivo metabolic processes, and the imaging of pyruvate (Pyr) metabolism is ideally suited to provide new insights into the ischemic heart and cardioactive effects of ethanol and other agents. Rodent studies have shown that the appearance of the bicarbonate signal following a bolus injection of hyperpolarized Pyr is due exclusively to the Pyr dehydrogenase flux (PDH), an important modulator of reperfusion injury. Our preliminary studies demonstrate that the flux of pyruvate-to-lactate is highly sensitive to coenzyme nicotinamide adenine dinucleotide (NADH) levels. The detoxification of aldehydes by ADLH2 results in the accumulation of NADH and plays a vital role in reducing tissue damage from oxidative stress. In vivo 13C-MRSI measurements of the conversion of Pyr to bicarbonate and lactate can provide critical insight into those molecular mechanisms of cardiac injury and cardioprotective therapies that involve PDH and ALDH2. This project is a unique opportunity to combine novel in vivo imaging technology with the development and assessment of cardioprotective agents. The ability to image noninvasively changes in PDH and ALDH2 activity would have significant import by enabling multiple metabolic measurements during ischemia and reperfusion injury experiments, facilitating longitudinal studies, and ultimately translating the resulting diagnostic tests and novel therapeutic agents to the clinic. Given the current state of development, translation of this new metabolic imaging capability from the laboratory to the clinic is anticipated within the next five years. PUBLIC HEALTH RELEVANCE: The cardioprotective effects of moderate alcohol consumption are well documented, but not fully understood. In vivo 13C magnetic resonance spectroscopic imaging of hyperpolarized pyruvate offers unprecedented opportunities to monitor real-time cardiac metabolism. However, the technology is inherently multidisciplinary - needing engineers and physicists to develop new acquisition methods, biochemists to investigate novel applications, and physicians to translate discoveries to the clinic. This proposal combines expertise from these disciplines and builds upon our prior work identifying the cardioprotective effects of ethanol by adding in vivo imaging measures of enzymatic pathways critical to reducing tissue damage from oxidative stress. This research will both help identify and characterize the underlying molecular mechanisms of cardiac ischemia and reperfusion injury and the cardioprotective effects of alcohol. The ultimate clinical goal is to develop metabolic imaging of hyperpolarized pyruvate as a diagnostic tool both to optimize choice of treatment and to monitor response to therapy.

描述（由申请人提供）：虽然人类流行病学和动物实验研究中记录了适量乙醇消耗的心脏保护作用，但过量乙醇消耗会导致心脏损伤、肝脏损伤和癌症。导致乙醇诱导的心脏保护和乙醇诱导的组织损伤的潜在细胞和分子机制很复杂且尚未完全了解。在我们的工作中，我们证明了乙醇保护作用的一个重要方面是通过直接预处理样机制最终激活醛脱氢酶（ALDH2）来实现的，ALDH2是去除氧化应激产生的有毒醛的主要线粒体酶。最近出现的超极化 13C 磁共振波谱成像 (MRSI) 为体内代谢过程的实时成像提供了前所未有的机会，丙酮酸 (Pyr) 代谢的成像非常适合为缺血性心脏以及乙醇和其他药物的心脏活性作用提供新的见解。啮齿动物研究表明，推注超极化 Pyr 后碳酸氢盐信号的出现完全是由于 Pyr 脱氢酶通量 (PDH) 所致，PDH 是再灌注损伤的重要调节剂。我们的初步研究表明，丙酮酸到乳酸的通量对辅酶烟酰胺腺嘌呤二核苷酸 (NADH) 水平高度敏感。 ADLH2 对醛的解毒导致 NADH 的积累，在减少氧化应激造成的组织损伤方面发挥着至关重要的作用。体内 Pyr 转化为碳酸氢盐和乳酸的 13C-MRSI 测量可以为涉及 PDH 和 ALDH2 的心脏损伤和心脏保护治疗的分子机制提供重要的见解。该项目是将新颖的体内成像技术与心脏保护剂的开发和评估相结合的独特机会。通过在缺血和再灌注损伤实验期间进行多种代谢测量，促进纵向研究，并最终将所得诊断测试和新型治疗剂转化为临床，对 PDH 和 ALDH2 活性变化进行无创成像的能力具有重要意义。鉴于目前的发展状况，预计这种新的代谢成像功能将在未来五年内从实验室转移到临床。 公众健康相关性：适量饮酒对心脏的保护作用已有充分记录，但尚未完全了解。超极化丙酮酸的体内 13C 磁共振波谱成像为监测实时心脏代谢提供了前所未有的机会。然而，该技术本质上是多学科的——需要工程师和物理学家开发新的采集方法，需要生物化学家研究新的应用，需要医生将发现转化为临床。该提案结合了这些学科的专业知识，并以我们之前的工作为基础，通过添加对减少氧化应激造成的组织损伤至关重要的酶途径的体内成像测量，确定了乙醇的心脏保护作用。这项研究将有助于识别和表征心脏缺血和再灌注损伤的潜在分子机制以及酒精的心脏保护作用。最终的临床目标是开发超极化丙酮酸的代谢成像作为诊断工具，以优化治疗选择并监测治疗反应。