Metabolic Imaging of the Cardioprotective Effects of Alcohol and ALDH2 Activators

Stanford University, Stanford CA

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Abstract

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.