Role of Reduced Lipoic Acid in the Redox Regulation of Mitochondrial Aldehyde Dehydrogenase (ALDH-2) Activity

Abstract

Chronic therapy with nitroglycerin results in a rapid development of nitrate tolerance, which is associated with an increased production of reactive oxygen species. We have recently shown that mitochondria are an important source of nitroglycerin-induced oxidants and that the nitroglycerin-bioactivating mitochondrial aldehyde dehydrogenase is oxidatively inactivated in the setting of tolerance. Here we investigated the effect of various oxidants on aldehyde dehydrogenase activity and its restoration by dihydrolipoic acid. In vivo tolerance in Wistar rats was induced by infusion of nitroglycerin (6.6 g/kg/min, 4 days). Vascular reactivity was measured by isometric tension studies of isolated aortic rings in response to nitroglycerin. Chronic nitroglycerin infusion lead to impaired vascular responses to nitroglycerin and decreased dehydrogenase activity, which was corrected by dihydrolipoic acid co-incubation. Superoxide, peroxynitrite, and nitroglycerin itself were highly efficient in inhibiting mitochondrial and yeast aldehyde dehydrogenase activity, which was restored by dithiol compounds such as dihydrolipoic acid and dithiothreitol. Hydrogen peroxide and nitric oxide were rather insensitive inhibitors. Our observations indicate that mitochondrial oxidative stress (especially superoxide and peroxynitrite) in response to organic nitrate treatment may inactivate aldehyde dehydrogenase thereby leading to nitrate tolerance. Glutathionylation obviously amplifies oxidative inactivation of the enzyme providing another regulatory pathway. Furthermore, the present data demonstrate that the mitochondrial dithiol compound dihydrolipoic acid restores mitochondrial aldehyde dehydrogenase activity via reduction of a disulfide at the active site and thereby improves nitrate tolerance.Organic nitrates such as nitroglycerin (glyceryl trinitrate, GTN) 3 have been used for over a century in the therapy of cardiovascular diseases like myocardial infarction, unstable angina, and arterial hypertension (1). However, the usefulness of organic nitrates is limited by tolerance, which develops shortly after onset of treatment. The mechanisms underlying nitrate tolerance remain only in part defined and are most likely multifactorial (2). Previously, we found that 3 days of nitrate treatment doubled vascular superoxide (O 2 . ) production (3), which was also found in human bypass material from GTNtreated patients (4). Chen et al. (5) identified the mitochondrial aldehyde dehydrogenase (ALDH-2) as a GTN-metabolizing enzyme and a possible important component in the processes leading to tolerance. This concept was supported by recent studies in ALDH-2-deficient mice (ALDH-2 Ϫ/Ϫ ) (6). Our laboratory further substantiated this concept in an animal model of in vivo tolerance and extended previous observations by demonstrating that mitochondria are a major source of reactive oxygen species formation in response to acute and chronic GTN challenges (7,8). The importance of the ALDH-2 concept for clinical nitrate tolerance was proven by two in...

Alpha-Lipoic Acid Ameliorates Oxidative Stress by Increasing Aldehyde Dehydrogenase-2 Activity in Patients with Acute Coronary Syndrome

“…Others have shown that over-expression of ALDH2 can downregulate ROS generation and protect against oxidative stress Choi et al 2011). Studies have also demonstrated that α-LA could increase ALDH2 activity by ~ 60% in isolated rat heart mitochondria (Wenzel et al 2007). Our results from the present study showed that α-LA was able to significantly reduce serum levels of 8-iso-PGF2α, which was accompanied by up-regulation of ALDH2 activity.…”

“…Recently, α-LA was reported to increase the activity of mitochondrial aldehyde dehydrogenase-2 (ALDH2) by ~ 60% in isolated rat heart mitochondria (Wenzel et al 2007). ALDH2, the main enzyme responsible for acetaldehyde oxidation in ethanol metabolism, is thought to be responsible for oxidation and detoxification of aromatic and aliphatic aldehydes (Bosron and Li 1986;Ohsawa et al 2003;Vasiliou and Nebert 2005;Bian et al 2010).…”

Decrease in endogenous CGRP release in nitroglycerin tolerance: Role of ALDH-2

“…Oxidative stress may be a decisive component in the development of nitrate tolerance (Munzel et al, 1999;Jurt et al, 2001;Csont and Ferdinandy, 2005;Wenzel et al, 2007). Recent studies have indicated that ALDH-2 is the main enzyme responsible for nitroglycerin bioactivation, and that inhibition of this enzyme contributes to nitrate tolerance (Chen et al, 2002;Sydow et al, 2004).…”

“…Recent studies have indicated that ALDH-2 is the main enzyme responsible for nitroglycerin bioactivation, and that inhibition of this enzyme contributes to nitrate tolerance (Chen et al, 2002;Sydow et al, 2004). There is evidence that oxidants can inactivate ALDH-2 directly and induce nitrate tolerance Wenzel et al, 2007). Oxidative stress may contribute directly to nitroglycerin tolerance, either by oxidative inhibition of ALDH-2 or perhaps by oxidizing key enzyme cofactors (Chen et al, 2002;Sydow et al, 2004;Daiber et al, 2004;Munzel et al, 2005).…”

“…Studies have showen that the mitochondrial isoform of aldehyde dehydrogenase (ALDH-2) is the main enzyme responsible for nitroglycerin bioactivation and has a specific role in cGMP-mediated, nitroglycerin-induced vasorelaxation (Chen et al, 2002;Sydow et al, 2004). It has been shown that nitrate tolerance is induced by inhibition of ALDH-2 (Chen et al, 2002;Sydow et al, 2004).Considerable evidence shows that nitrate tolerance is closely related to oxidative stress induced by an increased production of reactive oxygen species (Munzel et al, 1999;Jurt et al, 2001;Csont and Ferdinandy, 2005;Wenzel et al, 2007). It is likely that nitroglycerin induces the production of reactive oxygen species, with a subsequent decrease in mitochondrial ALDH-2 activity, resulting in nitrate tolerance (Chen et al, 2002;Sydow et al, 2004).…”