Biochemical and Biophysical Research Communications
ALDH-2 deficiency increases cardiovascular oxidative stress---Evidence for indirect antioxidative properties
Section snippets
Materials and methods
Animals and in vivo treatment. Young adult (10weeks) male ALDH-2−/− mice were age matched with C57Bl6 mice (wild type, WT). The generation of the ALDH-2 null mutant was described elsewhere [19]. Mice were equipped with micro osmotic pumps from Alzet (Cupertino, CA) containing 450 mM GTN solved in ethanol (undiluted, e.g. 100 μg/h/4d, diluted 1:1 with ethanol, e.g. 50 μg/h/4d, diluted 1:9, e.g. 10 μg/h/4d) or ethanol as a control. Mice were also treated in vivo with acetaldehyde (1.2 μl/d s.c. for 3
Activity and antioxidant capacities of human ALDH-2
The isolated and purified human ALDH-2 enzyme was tested with regard to its potential antioxidant properties. Compared to equimolar amounts of glutathione (GSH), dithiothreitol (DTT), and cysteine, ALDH-2 did not differ in its peroxynitrite scavenging properties (see Fig. 1A). Additionally, the ROS formation of isolated rat cardiac mitochondria from untreated Wistar rats was not increased upon in vitro inhibition of ALDH-2 by the selective inhibitor, daidzin (200 μM, see Fig. 1B). Finally, acute
Discussion
The main finding of our study is, that the mitochondrially located enzyme ALDH-2 seems to provide indirect antioxidant properties presumably by preventing the accumulation of toxic aldehydes rather than direct ROS scavenging activity based on its chemical structure. This explains best the observed more pronounced tolerance in response to in vivo nitroglycerin administration in ALDH-2−/− mice compared to WT but lack of any significant differences upon acute challenges with acetaldehyde, GTN or
Acknowledgments
We thank Dr. Ho and Prof. Weiner (Purdue University, West Lafayette, USA) for providing the human recombinant ALDH-2 plasmid. The expert technical assistance of Jörg Schreiner is gratefully appreciated. The financial support by the German Research Foundation (SFB 553 to A.D. and T.M.), by MAIFOR grants from the University Hospital Mainz (A.D. and P.W.) and by the Robert-Müller-Foundation (T.M. and A.D.) is gratefully acknowledged. This report contains results that are part of the thesis work of
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2019, Chemico-Biological InteractionsCitation Excerpt :Another mechanism by which DOX may cause elevated ROS levels is through dysregulation of antioxidant enzymes, such as glutathione peroxidase-1, which is readily inactivated upon exposure to DOX in cardiac tissue [9], while glutathione peroxidase-1 deficiency in mice was shown to increase the susceptibility to DOX-induced cardiotoxicity and overexpression of glutathione peroxidase-1 rescued the cardiac phenotype. In addition, it has been demonstrated that up-regulation of the mitochondrial antioxidant enzyme manganese superoxide dismutase (SOD2) counteracted cardiotoxic effects induced by DOX exposure [10], whereas deficiency in mitochondrial aldehyde dehydrogenase 2, which removes toxic aldehydes such as 4-hydroxynonenal resulting from lipid peroxidation, rendered mice more susceptible to DOX-induced cardiac and vascular damage [11]. Of note, genetic deletion of SOD2 in mice leads to prenatal or premature death of the animals, due to cardiomyocyte damage and dilated cardiomyopathy [12,13].
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These authors contributed equally to this work.