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, ?PKC. 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 ?PKC and ALDH2 activity, using genetically manipulated mice (AIM 1A). We will next identify the mechanisms that enable ethanol-induced entry of the cytosolic ?PKC 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 ?PKC-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 ?PKC- 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 #
3R37AA011147-13S1
Application #
7860783
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Orosz, Andras
Project Start
2009-07-15
Project End
2011-02-28
Budget Start
2009-07-15
Budget End
2011-02-28
Support Year
13
Fiscal Year
2009
Total Cost
$230,797
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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:
Hung, Chung-Lieh; Chang, Shun-Chuan; Chang, Sheng-Hsiung et al. (2017) Genetic Polymorphisms of Alcohol Metabolizing Enzymes and Alcohol Consumption are Associated With Asymptomatic Cardiac Remodeling and Subclinical Systolic Dysfunction in Large Community-Dwelling Asians. Alcohol Alcohol 52:638-646
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

Showing the most recent 10 out of 54 publications