A brief exposure to low levels of ethanol (10-50 mM) prior to cardiac ischemia reduces infarct size by ~60% in a process that is dependent on activation of epsilon protein kinase C, ePKC. We showed that activation of the mitochondrial enzyme, aldehyde dehydrogenase 2, ALDH2, is required and sufficient for ethanol-lnduced cardiac protection from ischemia;treatment with a novel activator of ALDH2 (Alda-1) mimics ethanol-lnduced cardioprotection. The importance of mitochondrial ALDH2 in human health is also suggested by the increased propensity of 40% of East Asians that carry an inactivating mutation in the ALDH2 gene, ALDH2*2, to have a variety of chronic diseases associated with oxidative stress and the resulting accumulation of toxic aldehydes, including myocardial infarction. In the next funding period, four aims will be addressed:
Aim 1 : Determine how ethanol-lnduced poundPKC-mediated activation of ALDH2 occurs. Mutagenesis and crystallographic studies, will help determine how ALDH2 phosphorylation enhances acetaldehyde catalysis.
Aim 2 : Determine if ethanol induces cardiac protection in ALDH2*2 mice from acute myocardial infarction, if ethanol-lnduced ePKC activation in these mice leads to phosphorylation of ALDH2*2 and if this phosphorylation increases the catalytic activity of the mutant enzyme Aim 3: Determine which proteins are modified by acetaldehyde and 4HNE and the functional consequence of these modifications.
Aim 4 : Identify pharmacological means to enhance aldehyde metabolism by changing the substrate preference of another ALDH enzyme. Together, these studies will elucidate fundamental processes associated with cytoprotection in animals with wild type and inactive (ALDH2*2) ALDH2 and how moderate ethanol exposure affects them. The proposed studies will also provide new tools and test their application as treatment for cardiac ischemia, using animal models.

Public Health Relevance

(See Instmctions): This proposed study will identify the mechanism by which small amounts of ethanol activates a cellular mechanism that protects from tissue injury by heart attack. The information gained from this study will help design better drugs to activate this protective mechanism in the general populations and in about 40% of East Asians, in which this protective mechanism is defective.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Method to Extend Research in Time (MERIT) Award (R37)
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Orosz, Andras
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Stanford University
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Joshi, Amit U; Saw, Nay L; Shamloo, Mehrdad et al. (2018) Drp1/Fis1 interaction mediates mitochondrial dysfunction, bioenergetic failure and cognitive decline in Alzheimer's disease. Oncotarget 9:6128-6143
Sarvi, Sana; Crispin, Richard; Lu, Yuting et al. (2018) ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells. Cell Chem Biol 25:1456-1469.e6
Chang, Peter Mu-Hsin; Chen, Che-Hong; Yeh, Chi-Chun et al. (2018) Transcriptome analysis and prognosis of ALDH isoforms in human cancer. Sci Rep 8:2713
Joshi, Amit U; Mochly-Rosen, Daria (2018) Mortal engines: Mitochondrial bioenergetics and dysfunction in neurodegenerative diseases. Pharmacol Res 138:2-15
Kiyuna, Ligia Akemi; Albuquerque, Rudá Prestes E; Chen, Che-Hong et al. (2018) Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities. Free Radic Biol Med 129:155-168
Saiki, Julie P; Cao, Hongbin; Van Wassenhove, Lauren D et al. (2018) Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes. Proc Natl Acad Sci U S A 115:6279-6284
Ueta, Cintia Bagne; Campos, Juliane Cruz; Albuquerque, Rudá Prestes E et al. (2018) Cardioprotection induced by a brief exposure to acetaldehyde: role of aldehyde dehydrogenase 2. Cardiovasc Res 114:1006-1015
Joshi, Amit U; Saw, Nay L; Vogel, Hannes et al. (2018) Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis. EMBO Mol Med 10:
Kim, Jeewon; Chen, Che-Hong; Yang, Jieying et al. (2017) Aldehyde dehydrogenase 2*2 knock-in mice show increased reactive oxygen species production in response to cisplatin treatment. J Biomed Sci 24:33
Hu, Yu-Feng; Chang, Yao-Ting; Lin, Yenn-Jiang et al. (2017) The roles of alcohol dehydrogenase in patients with atrial fibrillation. Pacing Clin Electrophysiol 40:1446-1453

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