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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA018681-03
Application #
8206864
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Orosz, Andras
Project Start
2010-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$478,120
Indirect Cost
$180,907
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Billingsley, Kelvin L; Josan, Sonal; Park, Jae Mo et al. (2014) Hyperpolarized [1,4-(13)C]-diethylsuccinate: a potential DNP substrate for in vivo metabolic imaging. NMR Biomed 27:356-62
Billingsley, Kelvin L; Park, Jae Mo; Josan, Sonal et al. (2014) The feasibility of assessing branched-chain amino acid metabolism in cellular models of prostate cancer with hyperpolarized [1-(13)C]-ketoisocaproate. Magn Reson Imaging 32:791-5
Josan, Sonal; Hurd, Ralph; Park, Jae Mo et al. (2014) Dynamic metabolic imaging of hyperpolarized [2-(13) C]pyruvate using spiral chemical shift imaging with alternating spectral band excitation. Magn Reson Med 71:2051-8
Josan, Sonal; Xu, Tao; Yen, Yi-Fen et al. (2013) In vivo measurement of aldehyde dehydrogenase-2 activity in rat liver ethanol model using dynamic MRSI of hyperpolarized [1-(13) C]pyruvate. NMR Biomed 26:607-12
Park, Jae Mo; Josan, Sonal; Grafendorfer, Thomas et al. (2013) Measuring mitochondrial metabolism in rat brain in vivo using MR Spectroscopy of hyperpolarized [2-ýýýýC]pyruvate. NMR Biomed 26:1197-203
Josan, Sonal; Park, Jae Mo; Hurd, Ralph et al. (2013) In vivo investigation of cardiac metabolism in the rat using MRS of hyperpolarized [1-13C] and [2-13C]pyruvate. NMR Biomed 26:1680-7
Xu, Tao; Mayer, Dirk; Gu, Meng et al. (2011) Quantification of in vivo metabolic kinetics of hyperpolarized pyruvate in rat kidneys using dynamic 13C MRSI. NMR Biomed 24:997-1005
MacKenzie, John D; Yen, Yi-Fen; Mayer, Dirk et al. (2011) Detection of inflammatory arthritis by using hyperpolarized 13C-pyruvate with MR imaging and spectroscopy. Radiology 259:414-20
Mayer, Dirk; Yen, Yi-Fen; Takahashi, Atsushi et al. (2011) Dynamic and high-resolution metabolic imaging of hyperpolarized [1-13C]-pyruvate in the rat brain using a high-performance gradient insert. Magn Reson Med 65:1228-33
Darpolor, Moses M; Yen, Yi-Fen; Chua, Mei-Sze et al. (2011) In vivo MRSI of hyperpolarized [1-(13)C]pyruvate metabolism in rat hepatocellular carcinoma. NMR Biomed 24:506-13

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