Mitochondrial aldehyde dehydrogenase (ALDH-2)--maker of and marker for nitrate tolerance in response to nitroglycerin treatment.
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.
II Medizinische Klinik, Labor für Molekulare Kardiologie, Johannes-Gutenberg-Universität, Mainz, Germany. daiber@uni-mainz.de
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Daiber
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Wenzel
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Oelze
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Schuhmacher
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Jansen
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Münzel
D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D004361:Drug Tolerance; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D009566:Nitrates / Q000627:therapeutic use*; D005996:Nitroglycerin / Q000627:therapeutic use*; D018384:Oxidative Stress
D009566:Nitrates; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005996:Nitroglycerin