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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AA011147-16
Application #
8278008
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Orosz, Andras
Project Start
1996-09-30
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
16
Fiscal Year
2012
Total Cost
$512,366
Indirect Cost
$192,224
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Woods, Christopher E; 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 134:961-77
Gross, Eric R; Zambelli, Vanessa O; Small, Bryce A et al. (2015) A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant. Annu Rev Pharmacol Toxicol 55:107-27
Chen, Che-Hong; Cruz, Leslie A; Mochly-Rosen, Daria (2015) Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo. Proc Natl Acad Sci U S A 112:3074-9
Gomes, Katia M S; Bechara, Luiz R G; Lima, Vanessa M et al. (2015) Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: benefits of Alda-1. Int J Cardiol 179:129-38
Kornfeld, Opher S; Hwang, Sunhee; Disatnik, Marie-Hélène et al. (2015) Mitochondrial reactive oxygen species at the heart of the matter: new therapeutic approaches for cardiovascular diseases. Circ Res 116:1783-99
Zambelli, Vanessa O; Chen, Che-Hong; Gross, Eric R (2015) Reactive aldehydes: an initial path to develop precision medicine for pain control. Ann Transl Med 3:258
Zambelli, Vanessa Olzon; Fernandes, Ana Carolina de Oliveira; Gutierrez, Vanessa Pacciari et al. (2014) Peripheral sensitization increases opioid receptor expression and activation by crotalphine in rats. PLoS One 9:e90576
Ebert, Antje D; Kodo, Kazuki; Liang, Ping et al. (2014) Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system. Sci Transl Med 6:255ra130
Kimble-Hill, Ann C; Parajuli, Bibek; Chen, Che-Hong et al. (2014) Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones. J Med Chem 57:714-22
Zambelli, Vanessa O; Gross, Eric R; Chen, Che-Hong et al. (2014) Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain. Sci Transl Med 6:251ra118

Showing the most recent 10 out of 27 publications