Publications by authors named "Toyoshi Isse"

4 Publications

  • Page 1 of 1

Mitochondrial aldehyde dehydrogenase 2 plays protective roles in heart failure after myocardial infarction via suppression of the cytosolic JNK/p53 pathway in mice.

J Am Heart Assoc 2014 Sep 18;3(5):e000779. Epub 2014 Sep 18.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (A.S., Y.Z., D.X., H.G., S.W., P.Z., Y.C., J.G.).

Background: Increasing evidence suggests a critical role for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in protection against cardiac injuries; however, the downstream cytosolic actions of this enzyme are largely undefined.

Methods And Results: Proteomic analysis identified a significant downregulation of mitochondrial ALDH2 in the heart of a rat heart failure model after myocardial infarction. The mechanistic insights underlying ALDH2 action were elucidated using murine models overexpressing ALDH2 or its mutant or with the ablation of the ALDH2 gene (ALDH2 knockout) and neonatal cardiomyocytes undergoing altered expression and activity of ALDH2. Left ventricle dilation and dysfunction and cardiomyocyte death after myocardial infarction were exacerbated in ALDH2-knockout or ALDH2 mutant-overexpressing mice but were significantly attenuated in ALDH2-overexpressing mice. Using an anoxia model of cardiomyocytes with deficiency in ALDH2 activities, we observed prominent cardiomyocyte apoptosis and increased accumulation of the reactive aldehyde 4-hydroxy-2-nonenal (4-HNE). We subsequently examined the impacts of mitochondrial ALDH2 and 4-HNE on the relevant cytosolic protective pathways. Our data documented 4-HNE-stimulated p53 upregulation via the phosphorylation of JNK, accompanying increased cardiomyocyte apoptosis that was attenuated by inhibition of p53. Importantly, elevation of 4-HNE also triggered a reduction of the cytosolic HSP70, further corroborating cytosolic action of the 4-HNE instigated by downregulation of mitochondrial ALDH2.

Conclusions: Downregulation of ALDH2 in the mitochondria induced an elevation of 4-HNE, leading to cardiomyocyte apoptosis by subsequent inhibition of HSP70, phosphorylation of JNK, and activation of p53. This chain of molecular events took place in both the mitochondria and the cytosol, contributing to the mechanism underlying heart failure.
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http://dx.doi.org/10.1161/JAHA.113.000779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323818PMC
September 2014

Effects and action mechanisms of Korean pear (Pyrus pyrifolia cv. Shingo) on alcohol detoxification.

Phytother Res 2012 Nov 26;26(11):1753-8. Epub 2012 Mar 26.

College of Pharmacy, Sookmyung Women's University, Seoul, 140-742, Republic of Korea.

Korean pear (Pyrus pyrifolia cv. Shingo) has been used as a traditional medicine for alleviating alcohol hangover. However, scientific evidence for its effectiveness or mechanism is not clearly established. To investigate its mechanism of alcohol detoxification, both in vitro and in vivo studies were performed with an aldehyde dehydrogenase 2 (ALDH2) alternated animal model. The pear extract (10 mL/kg bw) was administered to Aldh2 normal (C57BL/6) and deficient (Aldh2 -/-) male mice. After 30 min, ethanol (1 g or 2 g/kg bw) was administered to the mice via gavage. Levels of alcohol and acetaldehyde in blood were quantified by GC/MS. First, it was observed that the pears stimulated both alcohol dehydrogenase (ADH) and ALDH activities by 2∼3-  and 1.3-fold in in vitro studies, respectively. Second, mouse PK data (AUC(∞) and C(max) ) showed that the pear extract decreased the alcohol level in blood regardless of ALDH2 genotype. Third, the pear increased the acetaldehyde level in blood in Aldh2 deficient mice but not in Aldh2 normal mice. Therefore, the consistent in vitro and in vivo data suggest that Korean pears stimulate the two key alcohol-metabolizing enzymes. These stimulations could be the main mechanism of the Korean pear for alcohol detoxification. Finally, the results suggest that polymorphisms of human ALDH2 could bring out individual variations in the effects of Korean pear on alcohol detoxification.
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http://dx.doi.org/10.1002/ptr.4630DOI Listing
November 2012

Aldehyde dehydrogenase-2 deficiency aggravates cardiac dysfunction elicited by endoplasmic reticulum stress induction.

Mol Med 2012 Jul 18;18:785-93. Epub 2012 Jul 18.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been characterized as an important mediator of endogenous cytoprotection in the heart. This study was designed to examine the role of ALDH2 knockout (KO) in the regulation of cardiac function after endoplasmic reticulum (ER) stress. Wild-type (WT) and ALDH2 KO mice were subjected to a tunicamycin challenge, and the echocardiographic property was examined. Protein levels of six items--78 kDa glucose-regulated protein (GRP78), phosphorylation of eukaryotic initiation factor 2 subunit α (p-eIF2α), CCAAT/enhancer-binding protein homologous protein (CHOP), phosphorylation of Akt, p47(phox) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and 4-hydroxynonenal--were determined by using Western blot analysis. Cytotoxicity and apoptosis were estimated using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay and caspase-3 activity, respectively. ALDH2 deficiency exacerbated cardiac contractile dysfunction and promoted ER stress after ER stress induction, manifested by the changes of ejection fraction and fractional shortening. In vitro study revealed that tunicamycin significantly upregulated the levels of GRP78, p-eIF2α, CHOP, p47(phox) NADPH oxidase and 4-hydroxynonenal, which was exacerbated by ALDH2 knockdown and abolished by ALDH2 overexpression, respectively. Overexpression of ALDH2 abrogated tunicamycin-induced dephosphorylation Akt. Inhibition of phosphatidylinositol 3-kinase using LY294002 did not affect ALDH2-conferred protection against ER stress, although LY294002 reversed the antiapoptotic action of ALDH2 associated with p47(phox) NADPH oxidase. These results suggest a pivotal role of ALDH2 in the regulation of ER stress and ER stress-induced apoptosis. The protective role of ALDH2 against ER stress-induced cell death was probably mediated by Akt via a p47(phox) NADPH oxidase-dependent manner. These findings indicate the critical role of ALDH2 in the pathogenesis of ER stress in heart disease.
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http://dx.doi.org/10.2119/molmed.2011.00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409283PMC
July 2012

Ethanol metabolism in ALDH2 knockout mice--blood acetate levels.

Leg Med (Tokyo) 2009 Apr 7;11 Suppl 1:S413-5. Epub 2009 Apr 7.

Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki, Kita, Kagawa 761-0793, Japan.

We described here blood acetate levels in aldehyde dehydrogenase 2 knockout (ALDH2 KO) male mice based on C57BL/6J strain after ethanol (EtOH) dosing (2 g/kg). Blood samples were collected at 30, 60, 90, 120 180, and 240 min after decapitation, and then EtOH, acetaldehyde (AcH) and acetate were determined by head-space gas chromatography. We found that blood acetate levels in ALDH2 KO mice were slightly lower than those in wild type (WT), whereas EtOH and AcH levels in ALDH2 KO were significantly higher than those in WT. These observations indicate that high EtOH, AcH and low acetate in the blood of ALDH2 KO are due to the deficient effect of ALDH2 enzyme activity.
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http://dx.doi.org/10.1016/j.legalmed.2009.02.043DOI Listing
April 2009
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