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.
(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.
|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