Metabolic Imaging of the Cardioprotective Effects of Alcohol and ALDH2 Activators

描述（由申请人提供）：尽管人类流行病学和动物实验研究中记录了适量乙醇摄入的心脏保护作用，但过量乙醇摄入可导致心脏损伤、肝损伤和癌症。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是复杂的，并没有完全理解。在我们的工作中，我们已经证明了乙醇的保护作用的一个重要方面是通过直接的预处理样机制最终激活醛脱氢酶（ALDH 2），这是一种主要的线粒体酶，用于清除氧化应激产生的有毒醛。最近出现的超极化13 C磁共振光谱成像（MRSI）提供了前所未有的机会，在体内代谢过程的实时成像，丙酮酸（Pyr）代谢的成像是理想的适合提供新的见解缺血性心脏和乙醇和其他药物的心脏活性的影响。啮齿动物研究表明，超极化Pyr推注后出现碳酸氢盐信号完全是由于Pyr脱氢酶通量（PDH），一种重要的再灌注损伤调节剂。我们的初步研究表明，乳酸的通量是高度敏感的辅酶烟酰胺腺嘌呤二核苷酸（NADH）的水平。ADLH 2对醛类的解毒导致NADH的积累，并在减少氧化应激引起的组织损伤中起着至关重要的作用。Pyr转化为碳酸氢盐和乳酸盐的体内13 C-MRSI测量可以提供对涉及PDH和ALDH 2的心脏损伤和心脏保护治疗的分子机制的关键见解。该项目是一个独特的机会，联合收割机结合新的体内成像技术的发展和评估的心脏保护剂。PDH和ALDH 2活性的非侵入性成像变化的能力将具有重要意义，通过在缺血和再灌注损伤实验期间实现多个代谢测量，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。鉴于目前的发展状况，预计在未来五年内，这种新的代谢成像能力将从实验室转移到临床。 公共卫生相关性：适量饮酒对心脏的保护作用已有很好的记录，但尚未完全了解。超极化丙酮酸盐的体内13 C磁共振光谱成像提供了前所未有的机会来监测实时心脏代谢。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获取方法，生物化学家研究新的应用，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，并建立在我们先前的工作基础上，通过增加对减少氧化应激引起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。这项研究将有助于确定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代谢成像作为诊断工具，以优化治疗选择和监测对治疗的反应。

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.