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Mitochondrial aldehyde dehydrogenase (ALDH-2)—Maker of and marker for nitrate tolerance in response to nitroglycerin treatment

https://doi.org/10.1016/j.cbi.2008.09.003Get rights and content

Abstract

The hemodynamic and anti-ischemic effects of nitroglycerin (GTN) are rapidly blunted as a result of the development of nitrate tolerance. Long-term nitrate treatment also is associated with decreased vascular responsiveness caused by changes in intrinsic mechanisms of the tolerant vasculature itself. According to the oxidative stress concept, increased vascular superoxide and peroxynitrite production as well as an increased sensitivity to vasoconstrictors secondary to activation of protein kinase C as well as vascular NADPH oxidases contribute to the development of tolerance. Recent experimental work has defined new tolerance mechanisms, including inhibition of the enzyme that bioactivates GTN (e.g. mitochondrial aldehyde dehydrogenase [ALDH-2]) and mitochondria as potential sources of reactive oxygen species (ROS). GTN-induced ROS inhibit the bioactivation of GTN by ALDH-2. Both mechanisms impair GTN bioactivation, and now converge at the level of ALDH-2 to support a new theory for GTN tolerance and GTN-induced endothelial dysfunction. The consequences of these processes for GTN downstream targets (e.g. soluble guanylyl cyclase, cyclic guanosine monophosphate-dependent protein kinase) and toxic effects contributing to endothelial dysfunction (e.g. prostacyclin synthase inhibition and NO synthase uncoupling) are discussed. Tolerance and endothelial dysfunction are distinct processes which rely on different sources of ROS and there is good evidence for a crosstalk between these distinct processes. Finally, we will address the question whether ALDH-2 inactivation by nitroglycerin could be a useful marker for clinical nitrate tolerance and discuss the redox-regulation of this enzyme by oxidative stress and dihydrolipoic acid.

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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