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Nitrate-based vasodilators inhibit multiple vascular aldehyde dehydrogenases

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Abstract

Nitrate-based vasodilators (NBVs) are commonly used to treat multiple sequelae of atherosclerosis. A commonly used NBV, glyceryl trinitrate (GTN) is bioactivated by mitochondrial, class 2 aldehyde dehydrogenase (ALDH2). ALDH2 and other ALDHs are NAD(P)+-dependent enzymes critical to the detoxification of cytotoxic lipid-aldehydes elevated in atherosclerotic lesions, such as trans-4-hydroxy-2-nonenal (HNE). The GTN bioactivation step, however, inactivates ALDH2 and may alter the metabolism of these aldehydes. In this study, we tested the hypothesis that multiple ALDH enzymes are inhibited by different NBVs. ALDH2, ALDH3A, and ALDH5A were present in aorta with ALDH2 and ALDH3A localized to the smooth muscle layers. GTN (1 μM) inhibited ALDH2 activity (55±6% of control) and ablated ALDH3 activity. In contrast, isosorbide-2,5-dinitrate (ISDN, 1 μM) inhibited ALDH3 activity (1.1±0.4% of control) but did not inhibit ALDH2 activity even up to 50 μM ISDN. In homogenates of rat aorta, GTN (1 μM) inhibited the NAD+-dependent (41±5% of control) and NADP+-dependent (25±6% of control) detoxification of HNE. The inhibition of ALDH3A, but not ALDH2, could be prevented by the addition of dithiothreitol. These studies demonstrate that GTN and ISDN possess selectivity for ALDH inactivation with different mechanisms of inactivation.

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References

  1. Ruef, J., Moser, M., Bode, C., Kubler, W., and Runge, M.S. (2001). 4-Hydroxynonenal induces apoptosis, NF-kappaB-activation and formation of 8-isoprostane in vascular smooth muscle cells. Basic Res. Cardiol. 96:143–150.

    Article  PubMed  CAS  Google Scholar 

  2. Palinski, W., Ord, V.A., Plump, A.S., Breslow, J.L., Steinberg, D., and Witztum, J.L. (1994). ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Arterioscler. Thromb. 14:605–616.

    PubMed  CAS  Google Scholar 

  3. Mak, S., Lehotay, D.C., Yazdanpanah, M., Azevedo, E.R., Liu, P.P., and Newton, G.E. (2000). Unsaturated aldehydes including 4-OH-nonenal are elevated in patients with congestive heart failure. J. Card. Fail. 6:108–114.

    PubMed  CAS  Google Scholar 

  4. Waddington, E.I., Croft, K.D., Sienuarine, K., Latham, B., and Puddey, I.B. (2003). Fatty acid oxidation products in human atherosclerotic plaque: an analysis of clinical and histopathological correlates. Atherosclerosis 167:111–120.

    Article  PubMed  CAS  Google Scholar 

  5. Cyrus, T., Pratico, D., Zhao, L., Witztum, J.L., Rader, D.J., Rokach, J., et al. (2001). Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e-deficient mice. Circulation 103: 2277–2282.

    PubMed  CAS  Google Scholar 

  6. Esterbauer, H., Schaur, R., and Zollner, H. (1991). Chemistry and biochemistry of 4-hydroxynonenal, malondialdehyde, and related aldehydes. Free Radic. Biol. Med. 11: 81–128.

    Article  PubMed  CAS  Google Scholar 

  7. Ruef, J., Rao, G.N., Li, F., Bode, C., Patterson, C., Bhatnagar, A., et al. (1998). Induction of rat aortic smooth muscle cell growth by the lipid peroxidation product 4-hydroxy-2-nonenal. Circulation 97:1071–1078.

    PubMed  CAS  Google Scholar 

  8. Uchida, K. (2003). 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Prog. Lipid Res. 42:318–343.

    Article  PubMed  CAS  Google Scholar 

  9. Levonen, A.L., Landar, A., Ramachandran, A., Ceaser, E.K., Dickinson, D.A., Zanoni, G., et al. (2004). Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. Biochem. J. 378: 373–382.

    Article  PubMed  CAS  Google Scholar 

  10. Ceaser, E.K., Moellering, D.R., Shiva, S., Ramachandran, A., Landar, A., Venkartraman, A., et al. (2004). Mechanisms of signal transduction mediated by oxidized lipids: the role of the electrophite-responsive proteome. Biochem. Soc. Trans. 32:151–155.

    Article  PubMed  CAS  Google Scholar 

  11. Kunstmann, S., Mertsch, K., Blasig, I.E., and Grune, T. (1996). High metabolic rates of 4-hydroxynonenal in brain capillary endothelial cells during hypoxia/reoxygenation. Brain Res. 740:353–355.

    Article  PubMed  CAS  Google Scholar 

  12. Srivastava, S., Conklin, D.J., Liu, S., Prakash, N., Boor, P.J., Srivastava, S.K., et al. (2001). Identification of biochemical pathways for the metabolism of oxidized low-density lipoprotein derived aldehyde-4-hydroxy trans-2-nonenal in vascular smooth muscle cells. Atherosclerosis 158:339–350.

    Article  PubMed  CAS  Google Scholar 

  13. Murphy, T.C., Amarnath, V., Gibson, K.M., and Picklo, M.J.S. (2003). Oxidation of 4-hydroxy-2-nonenal by succinic semialdehyde dehydrogenase (ALDH5A). J. Neurochem. 86:298–305.

    Article  PubMed  CAS  Google Scholar 

  14. Mitchell, D. and Petersen, D. (1987). The oxidation of a,b,unsaturated aldehydic products in lipid peroxidation by rat liver aldehyde dehydrogenases. Toxicol. Appl. Pharmacol. 87:403–410.

    Article  PubMed  CAS  Google Scholar 

  15. Hartley, D., Ruth, J., and Petersen, D. (1995). The hepatocellular metabolism of 4-hydroxynonenal by alcohol dehydrogenase, aldehyde dehydrogenase, and glutathione s-transferase. Arch. Biochem. Biophys. 316:197–205.

    Article  PubMed  CAS  Google Scholar 

  16. Townsend, A.J., Leone-Kabler, S., Haynes, R.L., Wu, Y., Szweda, L., and Bunting, K.D. (2001). Selective protection by stably transfected human ALDH3A1 (but not human ALDH1A1) against toxicity of aliphatic aldehydes in V79 cells. Chem. Biol. Interact. 130–132:261–273.

    Article  PubMed  Google Scholar 

  17. Pappa, A., Estey, T., Manzer, R., Brown, D., and Vasiliou, V. (2003). Human aldehyde dehydrogenase 3A1 (ALDH3A1): biochemical characterization and immunohistochemical localization in the cornea. Biochem. J. 376: 615–623.

    Article  PubMed  CAS  Google Scholar 

  18. Lindahl, R. and Petersen, D.R. (1991). Lipid aldehyde oxidation as a physiological role for class 3 aldehyde dehydrogenases. Biochem. Pharmacol. 41:1583–1587.

    Article  PubMed  CAS  Google Scholar 

  19. Chambliss, K.L., Caudle, D.L., Hinson, D.D., Moomaw, C.R., Slaughter, C.A., Jakobs, C., et al. (1995). Molecular cloning of the mature NAD(+)-dependent succinic semialdehyde dehydrogenase from rat and human. cDNA isolation, evolutionary homology, and tissue expression. J. Biol. Chem. 270:461–467.

    Article  PubMed  Google Scholar 

  20. Chambliss, K.L., Zhang, Y.A., Rossier, E., Vollmer, B., and Gibson, K.M. (1995). Enzymatic and immunologic identification of succinic semialdehyde dehydrogenase in rat and human neural and nonneural tissues. J. Neurochem. 65:851–855.

    Article  PubMed  CAS  Google Scholar 

  21. DiFabio, J., Ji, Y., Vasiliou, V., Thatcher, G.R., and Bennett, B.M. (2003). Role of mitochondrial aldehyde dehydrogenase in nitrate tolerance. Mol. Pharmacol. 64:1109–1116.

    Article  PubMed  CAS  Google Scholar 

  22. Daiber, A., Oelze, M., Coldewey, M., Bachschmid, M., Wenzel, P., Sydow, K., et al. (2004). Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythrityl tetranitrate (PETN) with other organic nitrates. Mol. Pharmacol. 66:1372–1382.

    Article  PubMed  CAS  Google Scholar 

  23. Sydow, K., Daiber, A., Oelze, M., Chen, Z., August, M., Wendt, M., et al. (2004). Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance. J. Clin. Invest. 113:482–489.

    Article  PubMed  CAS  Google Scholar 

  24. Chen, Z., Zhang, J., and Stamler, J.S. (2002). Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc. Natl. Acad. Sci. USA 99:8306–8311.

    Article  PubMed  CAS  Google Scholar 

  25. Pietruszko, R., Mukerjee, N., Blatter, E.E., and Lehmann, T. (1995). Nitrate esters as inhibitors and substrates of aldehyde dehydrogenase. Adv. Exp. Med. Biol. 372:25–34.

    PubMed  CAS  Google Scholar 

  26. Towell, J., Garthwaite, T., and Wang, R. (1985). Erythrocyte aldehyde dehydrogenase and disulfiram-like side effects of hypoglycemics and antianginals. Alcohol. Clin. Exp. Res. 9:438–442.

    PubMed  CAS  Google Scholar 

  27. Murphy, T.C., Amarnath, V., and Picklo, M.J.S. (2003). Mitochondrial oxidation of 4-hydroxynonenal in rat cerebral cortex. J. Neurochem. 84:1313–1321.

    Article  PubMed  CAS  Google Scholar 

  28. Picklo, M.J., Olson, S.J., Markesbery, W.R., and Montine, T.J. (2001). Expression and activities of aldo-keto oxidoreductases in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60:686–695.

    PubMed  CAS  Google Scholar 

  29. Boesch, J.S., Lee, C., and Lindahl, R.G. (1996). Constitutive expression of class 3 aldehyde dehydrogenase in cultured rat corneal epithelium. J. Biol. Chem. 271:5150–5157.

    Article  PubMed  CAS  Google Scholar 

  30. DeMaster, E.G., Redfern, B., and Nagasawa, H.T. (1998). Mechanisms of inhibition of aldehyde dehydrogenase by nitroxyl, the active metabolite of the alcohol deterrent agent cyanamide. Biochem. Pharmacol. 55:2007–2015.

    Article  PubMed  CAS  Google Scholar 

  31. Wymore, T., Nicholas, H.B., and Hempel, J. (2001). Molecular dynamics simulation of class 3 aldehyde dehydrogenase. Chem. Biol. Interact. 130–132:201–207.

    Article  PubMed  Google Scholar 

  32. Hellstrom, E. and Tottmar, O. (1982). Effects of aldehyde dehydrogenase inhibitors on enzymes involved in the metabolism of biogenic aldehydes in rat liver and brain. Biochem. Pharmacol. 31:3899–3905.

    Article  PubMed  CAS  Google Scholar 

  33. Vasiliou, V. and Marselos, M. (1989). Changes in the inducibility of a hepatic aldehyde dehydrogenase by various effectors. Arch. Toxicol. 63:221–225.

    Article  PubMed  CAS  Google Scholar 

  34. Farres, J., Guan, K.L., and Weiner, H. (1989). Primary structures of rat and bovine liver mitochondrial aldehyde dehydrogenases deduced from cDNA sequences. Eur. J. Biochem. 180:67–74.

    Article  PubMed  CAS  Google Scholar 

  35. Ryzlak, M.T. and Pietruszko, R. (1987). Purification and characterization of aldehyde dehydrogenase from human brain. Arch. Biochem. Biophys. 255:409–418.

    Article  PubMed  CAS  Google Scholar 

  36. Chambliss, K.L. and Gibson, K.M. (1992). Succinic semialdehyde dehydrogenase from mammalian brain: subunit analysis using polyclonal antiserum. Int. J. Biochem. 24: 1493–1499.

    Article  PubMed  CAS  Google Scholar 

  37. Lindros, K.O., Oinonen, T., Kettunen, E., Sippel, H., Muro-Lupori, C., and Koivusalo, M. (1998). Aryl hydrocarbon receptor-associated genes in rat liver: regional coinduction of aldehyde dehydrogenase 3 and glutathione transferase Ya. Biochem. Pharmacol. 55:413–421.

    Article  PubMed  CAS  Google Scholar 

  38. Bassi, A.M., Ledda, S., Penco, S., Menini, S., Muzio, G., Canuto, R., et al. (2000). Changes of CYP1A1, GST, and ALDH3 enzymes in hepatoma cell lines undergoing enhanced lipid peroxidation. Free Radic. Biol. Med. 29:1186–1196.

    Article  PubMed  CAS  Google Scholar 

  39. Vasiliou, V., Buetler, T., Eaton, D.L., and Nebert, D.W. (2000). Comparison of oxidative stress response parameters in newborn mouse liver versus simian virus 40 (SV40)-transformed hepatocyte cell lines. Biochem. Pharmacol. 59:703–712.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry, University of North Dakota, Grand Forks, ND

    Matthew J. Picklo Sr. PhD

  2. Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, 501 North Columbia Road, 58203, Grand Forks, ND

    Tonya C. Murphy, Roberta Arntzen & Matthew J. Picklo Sr. PhD

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  1. Tonya C. Murphy
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  2. Roberta Arntzen
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  3. Matthew J. Picklo Sr. PhD
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Correspondence to Matthew J. Picklo Sr. PhD.

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Murphy, T.C., Arntzen, R. & Picklo, M.J. Nitrate-based vasodilators inhibit multiple vascular aldehyde dehydrogenases. Cardiovasc Toxicol 5, 321–332 (2005). https://doi.org/10.1385/CT:5:3:321

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  • DOI: https://doi.org/10.1385/CT:5:3:321

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