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)：虽然在人类流行病学和动物实验研究中证明了适度饮酒对心脏的保护作用，但过量饮酒会导致心脏损伤、肝脏损伤和癌症。导致乙醇诱导的心脏保护和酒精诱导的组织损伤的潜在细胞和分子机制是复杂的，还不完全清楚。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一种直接的类似预适应的机制，最终激活乙醛脱氢酶(ALDH2)，这是清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)为实时成像体内代谢过程提供了前所未有的机会，而丙酮酸(PYR)代谢成像非常适合于为乙醇和其他药物的缺血心脏和心脏活动效应提供新的见解。啮齿类动物的研究表明，注射超极化PYR后出现碳酸氢盐信号完全是由于PYR脱氢酶通量(PDH)，它是再灌注损伤的重要调节因子。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对醛的解毒作用导致NADH的积累，在减轻氧化应激对组织的损伤方面起着至关重要的作用。体内~(13)C-MRSI测量PYR转化为重碳酸盐和乳酸的过程，可以为心脏损伤的分子机制和涉及PDH和ALDH2的心脏保护治疗提供关键的洞察力。该项目是将新的活体成像技术与心脏保护剂的开发和评估相结合的独特机会。对PDH和ALDH2活性的非侵入性变化进行成像的能力将具有重要意义，因为它能够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，并最终将所产生的诊断测试和新型治疗药物转化为临床。鉴于目前的发展状况，这种新的代谢成像能力有望在未来五年内从实验室转移到临床。 与公共健康相关：适度饮酒对心脏的保护作用有很好的记录，但还没有完全了解。在体内，超极化丙酮酸的13C磁共振波谱成像为实时监测心脏代谢提供了前所未有的机会。然而，这项技术本质上是多学科的--需要工程师和物理学家来开发新的获取方法，需要生物化学家来研究新的应用，需要医生来将发现转化为临床。这项建议结合了这些学科的专业知识，并建立在我们之前工作的基础上，通过增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措施来确定乙醇的心脏保护作用。这项研究将有助于识别和表征心肌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一种诊断工具，以优化治疗选择和监测治疗反应。