Ten years ago, we found that a brief exposure to 10-50 mM ethanol prior to cardiac ischemia reduces infarct size by ~70% in a process that is dependent on activation of epsilon protein kinase C, 5PKC. In the past funding period, we found that activation of the mitochondrial enzyme, aldehyde dehydrogenase 2, ALDH2, appears to be required and sufficient for ethanol-induced cardiac protection from ischemia. 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. We plan to determine whether ethanol-induced cytoprotection requires 5PKC and ALDH2 activity, using genetically manipulated mice (AIM 1A). We will next identify the mechanisms that enable ethanol-induced entry of the cytosolic 5PKC into the mitochondria, where ALDH2 is found, (AIM 1B). We will then determine whether ALDH2 activation by ethanol and other activators reduces aldehydic adduct loads to reduce cytotoxicity (AIM 1C). We will determine whether acetaldehyde, which accumulates on ethanol treatment, contributes to ethanol-induced cardioprotection (AIM 1D) and determine whether ethanol- induced and 5PKC-mediated phosphorylation of ALDH2 protects ALDH2 activity from inactivation by long chain aldehydes and whether the effect is additive with new small molecule activators of ALDH2, called Alda (AIM 1E).
In AIM 2, we will study the loss of ethanol-induced cardioprotection due to ALDH2 inhibition by nitroglycerine (NTG). We will identify small molecule that inhibit NTG-induced ALDH2 inactivation (NTG tolerance) (AIM 2A, B) and will determine the effect of NTG tolerance inhibitors on ethanol-induced 5PKC- mediated cardioprotection from acute ischemic damage ex vivo and in animal models (AIM 2C). Together, these studies will elucidate fundamental processes associated with cytoprotection in animals with wildtype and inactive (ALDH2*2) form of ALDH2 and how moderate ethanol consumption affects them. Our studies will also provide new tools and test their application as treatment for cardiac ischemia using animal models.

Public Health Relevance

Acute exposure to moderate levels of ethanol protects the heart from ischemic injury, such as that occurring during coronary bypass surgery. We recently found that a major enzyme involved in metabolizing toxins that accumulate during oxidative stress is critical for this ethanol-induced cardioprotection. Because of the potential toxic and addictive effects of ethanol, we searched for new compounds that directly activate this detoxifying enzyme and plan to test their efficacy in animal models of cardiac ischemia. This study may eventually provide new means to induce cytoprotection in humans subjected to ischemic insult.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Orosz, Andras
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Chang, Jeffrey S; Hsiao, Jenn-Ren; Chen, Che-Hong (2017) ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective. J Biomed Sci 24:19
Ueta, Cintia B; Gomes, Katia S; Ribeiro, Márcio A et al. (2017) Disruption of mitochondrial quality control in peripheral artery disease: New therapeutic opportunities. Pharmacol Res 115:96-106
Nene, Aishwarya; Chen, Che-Hong; Disatnik, Marie-Hélène et al. (2017) Aldehyde dehydrogenase 2 activation and coevolution of its ?PKC-mediated phosphorylation sites. J Biomed Sci 24:3
Maity, Santanu; Sadlowski, Corinne M; George Lin, Jung-Ming et al. (2017) Thiophene bridged aldehydes (TBAs) image ALDH activity in cells via modulation of intramolecular charge transfer. Chem Sci 8:7143-7151
Woods, Christopher; Shang, Ching; Taghavi, Fouad et al. (2016) In Vivo Post-Cardiac Arrest Myocardial Dysfunction Is Supported by Ca2+/Calmodulin-Dependent Protein Kinase II-Mediated Calcium Long-Term Potentiation and Mitigated by Alda-1, an Agonist of Aldehyde Dehydrogenase Type 2. Circulation 134:961-977
Hurt, Carl M; Lu, Yao; Stary, Creed M et al. (2016) Transient Receptor Potential Vanilloid 1 Regulates Mitochondrial Membrane Potential and Myocardial Reperfusion Injury. J Am Heart Assoc 5:
Nakano, Yukiko; Ochi, Hidenori; Onohara, Yuko et al. (2016) Genetic variations of aldehyde dehydrogenase 2 and alcohol dehydrogenase 1B are associated with the etiology of atrial fibrillation in Japanese. J Biomed Sci 23:89
Joshi, Amit U; Kornfeld, Opher S; Mochly-Rosen, Daria (2016) The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained. Cell Calcium 60:218-34
Yu, Yu-Hsiang; Liao, Pei-Ru; Guo, Chien-Jung et al. (2016) PKC-ALDH2 Pathway Plays a Novel Role in Adipocyte Differentiation. PLoS One 11:e0161993
Van Wassenhove, Lauren D; Mochly-Rosen, Daria; Weinberg, Kenneth I (2016) Aldehyde dehydrogenase 2 in aplastic anemia, Fanconi anemia and hematopoietic stem cells. Mol Genet Metab 119:28-36

Showing the most recent 10 out of 41 publications