Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acetaldehyde, the major metabolite of ethanol, which is far more toxic and reactive than ethanol, may be responsible for alcohol-induced cardiac damage. This study was designed to examine the impact of facilitated acetaldehyde metabolism using transfection of human aldehyde dehydrogenase-2 (ALDH2) transgene on acetaldehyde- and ethanol-induced cell injury. Fetal human cardiac myocytes were transfected with ALDH2, the efficacy of which was verified by flow cytometry, Western blot and ALDH2 activity assays. Generation of reactive oxygen species (ROS) was detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA). Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride (DAPI) fluorescence microscopy, quantitative DNA fragmentation ELISA and caspase 3 activity. Acetaldehyde and ethanol elicited overt ROS generation and apoptosis in human cardiac myocytes following 24-48 h of incubation. Immunostaining revealed activation of the MAP kinase cascades ERK1/2, SAPK/JNK and p38 MAP kinase in acetaldehyde-treated myocytes. Interestingly, ALDH2 transgene significantly attenuated acetaldehyde-induced ROS generation, apoptosis and phosphorylation of ERK1/2 and SAPK/JNK. Time-dependent response (0-12 h) revealed ROS accumulation and activation of MAP kinases prior to acetaldehyde-induced apoptosis. In addition, acetaldehyde-induced ROS generation and apoptosis were antagonized by non-enzymatic antioxidants. Our results suggested that ALDH2 transgene overexpression may effectively alleviate acetaldehyde-elicited cell injury through an ERK1/2 and SPAK/JNK-dependent mechanism. Our data are consistent with the notion of acetaldehyde as a contributor to alcoholic cardiomyopathy and implicate the therapeutic potential of ALDH2 enzyme in alcoholic complications.
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PMID:Attenuation of acetaldehyde-induced cell injury by overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene in human cardiac myocytes: role of MAP kinase signaling. 1640 13

Ethanol modulates mitogen-activated protein kinases (MAPKs). We have now investigated the influence of ethanol and its metabolite, acetaldehyde on histone H3 phosphorylation to ascertain downstream targets of MAPKs. In primary culture of rat hepatocytes, ethanol and acetaldehyde increased phosphorylation of nuclear histone H3 at serine 10 and serine 28. Specific inhibitors of p38 MAPK, SB203580, PD169316 and SB202190 blocked this phosphorylation. The inactive analogue, SB202474 had no effect. In contrast, c-Jun N-terminal kinase (JNK) inhibitor, SP600125 or MAP/ERK kinase (MEK) 1/2 inhibitor, PD98059 had no effect on the histone H3 phosphorylation. The p38 MAPK activation correlated with upstream activation of MAPK kinase (MKK) 3/6 but was independent of protein synthesis. In the nuclear fraction, the phosphorylation of p38 MAPK and its protein level increased with peak activation at 24 h by ethanol and at 30 min by acetaldehyde. These responses were ethanol and acetaldehyde dose dependent. Surprisingly, the phosphorylation of p38 MAPK was undetectable in the cytosolic fraction suggesting a subcellular selectivity of p38 MAPK signaling. The phosphorylation of JNK and p42/44 MAPK and their protein levels also increased in the nuclear fraction. Although ethanol caused translocation of all three major MAPKs (p42/44 MAPK, JNK, p38 MAPK) into the nucleus, histone H3 phosphorylation at serine 10 and serine 28 was mediated by p38 MAPK. This histone H3 phosphorylation had no influence on ethanol and acetaldehyde induced apoptosis. These studies demonstrate for the first time that ethanol and acetaldehyde stimulated phosphorylation of histone H3 at serine 10 and serine 28 are downstream nuclear response mediated by p38 MAPK in hepatocytes.
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PMID:Histone H3 phosphorylation at serine 10 and serine 28 is mediated by p38 MAPK in rat hepatocytes exposed to ethanol and acetaldehyde. 1764 7