Mini-reviewMitochondrial aldehyde dehydrogenase (ALDH-2)—Maker of and marker for nitrate tolerance in response to nitroglycerin treatment
Section snippets
Clinical nitrate tolerance
A major therapeutic limitation inherent to organic nitrates is the development of tolerance which occurs during chronic treatment with these agents (for reviews see Refs. [1], [2]). The mechanisms underlying nitrate tolerance remain poorly defined, and are likely multifactorial. One mechanism seems to be a diminished bioconversion of nitroglycerin to its active vasodilator metabolite [3]. Other mechanisms likely include neurohumoral adaptations, e.g., increases in plasma volume [4], activation
Mitochondrial oxidative stress and mitochondrial aldehyde dehydrogenase
The mitochondrial aldehyde dehydrogenase (ALDH-2) is an important enzyme for the detoxification of aldehydes to the corresponding carboxylic acid. Besides the well-known aldehyde oxidizing activity which relies on the co-factor NAD+, ALDH-2 also exerts unspecific esterase activity leading to cleavage of carboxylic acid esters but also esters of inorganic acids without requirement of co-factors. After Towell et al. already reported in 1985 that anti-anginals have antabus-like effects in red
Role of ALDH-2 for clinical tolerance in humans
Recent studies indicate that the long-term use of mononitrates and dinitrates in patients with coronary artery disease after an acute myocardial infarction might be even deleterious for patients with ischemic heart disease [39], [40]. Although the mechanisms underlying nitrate tolerance are likely multifactorial, recent studies indicate that two mechanisms such as stimulation of vascular production of reactive oxygen species as well as an inhibition of the GTN bioactivating mitochondrial enzyme
Acknowledgements
The financial support by the German Research Foundation (SFB 553 to A.D. and T.M.), by MAIFOR and Förderfonds grants from the University Hospital Mainz (A.D.) and by the Robert-Müller-Foundation (T.M. and A.D.) is gratefully acknowledged.
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2020, Free Radical Biology and MedicineCitation Excerpt :Since oxidation and inactivation of ALDH-2 cause accumulation of toxic aldehydes such as 4-hydroxynonenal [285], this may lead to cardiac dysfunction [286]. Of note, α-lipoic acid is a potent activator of ALDH-2 and thereby improves nitroglycerin vasodilatory and anti-ischaemic effects in rat models [283,287] and humans [288]. In addition, α-lipoic acid improves diabetic polyneuropathy [176] by decreasing AGE levels and downstream RAGE signalling [289], and ameliorates endothelial function in patients with diabetes [290].
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2013, Nitric Oxide - Biology and ChemistryCitation Excerpt :In 2002, Chen and Stamler first demonstrated that mitochondrial aldehyde dehydrogenase (ALDH2) was able to bioactivate NTG to release NO [1,2]. These results were later confirmed by an ex vivo aortic relaxation assay [3,4]. Recently, Berretta et al. [5] showed that in mouse aorta, NTG bioactivation was mainly contributed by cytosolic rather than mitochondrial ALDH2.
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