Skip to main content
SpringerLink
Log in

Cardiac toxic effects of trans-2-hexenal are mediated by induction of cardiomyocyte apoptotic pathways

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Aldehydes are ubiquitous pollutants with well-indicated but ill-defined cardiovascular toxicity. To investigate the direct toxic effects of environmental aldehyde exposure on the myocardium, 8-wk-old male ICR (Institute of Cancer Research) strain mice were gavage fed trans-2-hexenal (0.1, 1, 10, or 50 mg/kg/wk) or corn oil (vehicle) for 4 wk, during which cardiac function, myocardial morphology, cardiomyocyte apoptosis, and the cytochrome c-mediated caspase activation apoptotic pathway were determined. Quantification by enzyme-linke immunosorbent assay (ELISA) revealed that aldehyde-protein adducts increase in mouse hearts following hexenal treatment, whereas echocardiographic analysis displayed a significant impairment of basal left-ventricular contractile function. Both histological analysis and TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling) staining indicated condensed nuclei and a significant increase in cardiomyocyte apoptosis in these mice, but immunohistochemistry-based confocal microscope revealed no marked myofibril disarray. Release of cytochrome c from mitochondria into the cytosol, concomitant with activation of caspase-3 and-9, was also found in hexenal-treated groups. In addition, isolated cardiac mitochondria formed hexenal-protein adducts when treated with hexenal, providing indirect evidence that the cardiac mitochondrion is one of primary subcellular targets of aldehyde toxins. These findings suggest that trans-2-hexenal exposure results in direct cardiac toxicity through, at least in part, induction of mitochondrial cytochrome c release-mediated apoptosis in cardiomyocytes, indicating that the cardiac mitochondrion is one of principal subcellular targets of aldehyde toxins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Committee on Aldehydes. (1981). Formaldehyde and Other Aldehydes. Board on Toxicology and Environmental Health Hazards, Assembly of Life Sciences, National Research Council, National Academy Press, Washington, DC, pp. 234–241.

    Google Scholar 

  2. Environmental Protection Agency. (1997). National Air Quality Standards for Particulate Matter. Environmental Protection Agency, Washington, DC.

    Google Scholar 

  3. Levine, R. J., Andjelkovich, D. A., and Shaw, L. K. (1984). The mortality of Ontario undertakers and a review of formaldehyde-related mortality studies. J. Occup. Med. 26:740–746.

    Article  PubMed  CAS  Google Scholar 

  4. Matanoski, G. M. and Schwartz, L. (1987). Mortality of workers in styrene-butadiene polymer production. J. Occup. Med. 29:675–680.

    PubMed  CAS  Google Scholar 

  5. Seaton, A., MacNee, W., Donaldson, K., and Godden, D. (1995). Particulate air pollution and acute health effects. Lancet 345:176–178.

    Article  PubMed  CAS  Google Scholar 

  6. Stewart, P. A., Schairer, C., and Blair, A. (1990). Comparison of jobs, exposures, and mortality risks for shortterm and long-term workers. J. Occup. Med. 32:703–708.

    PubMed  CAS  Google Scholar 

  7. Walrath, J. and Fraumeni, J. F. Jr. (1984). Cancer and other causes of death among embalmers. Cancer Res. 44:4638–4641.

    PubMed  CAS  Google Scholar 

  8. Magari, S. R., Hauser, R., Schwartz, J., Williams, P. L., Smith, T. J., and Christiani, D. C. (2001). Association of heart rate variability with occupational and environmental exposure to particulate air pollution. Circulation 104: 989–991.

    Google Scholar 

  9. Peters, A., Dockery, D. W., Muller, J. E., and Mittleman, M. A. (2001). Increased particulate air pollution and the triggering of myocardial infarction. Circulation 103:2810–2815.

    PubMed  CAS  Google Scholar 

  10. Elsässer, A., Suzuki, K., Lorenz-Meyer, S., Bode, C., and Schaper, J. (2001). The role of apoptosis in myocardial ischemia: a critical appraisa. Basic Res. Cardiol. 96:219–226.

    Article  PubMed  Google Scholar 

  11. Olivetti, G., Abbi, R., Quaini, F., Kajstura, J., Chen, W., Nitahara, J. A., et al. (1997). Apoptosis in the failure human heart. N. Engl. J. Med. 336:1131–1141.

    Article  PubMed  CAS  Google Scholar 

  12. Haynes, R. L., Brune, B., and Townsend, A. J. (2001). Apoptosis in RAW 264.7 cells exposed to 4-hydroxy-2-nonenal: dependence on cytochrome c release but not p53 accumulation. Free Radic. Biol. Med. 30:884–894.

    Article  PubMed  CAS  Google Scholar 

  13. Herbst, U., Toborek, M., Kaiser, S., Mattson, M. P., and Hennig, B. (1994). 4-hydroxynonenal induces dysfunction and apoptosis of cultured endothelial cells. J. Cell Physiol. 181:295–303.

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  15. Zhang, W., He, Q., Chan, L. L., Zhou, F., El Naghy, M., Thompson, E. B., et al. (2001). Involvement of caspases in 4-hydroxy-alkenal-induced apoptosis in human leukemic cells. Free Radic. Biol. Med. 30:699–706.

    Article  PubMed  CAS  Google Scholar 

  16. Ji, C., Amarnath, V., Pietenpol, J.A., and Marnett, L.J. (2001). 4-Hydroxynonenal induces apoptosis via caspase-3 activation and cytochrome crelease. Chem. Res. Toxicol. 14:1090–1096.

    Article  PubMed  CAS  Google Scholar 

  17. Liu, W., Kato, M., Akhand, A.A., Hayakawa, A., Suzuki, H., Miyata, T., et al. (2000). 4-Hydroxynonenal induces a cellular redox status-related activation of the caspase cascade for apoptotic cell death. J. Cell. Sci. 113:635–642.

    PubMed  CAS  Google Scholar 

  18. Esterbauer, H. (1993). Cytotoxicity and genotoxicity of lipid-oxidation products. Am. J. Clin. Nutr. 57:S779-S786.

    Google Scholar 

  19. Yazdanpanah, M., Luo, X.P., Lau, R., Greenberg, M., Fisher, L.J., and Lehotay, D.C. (1997). Cytotoxic aldehydes as possible markers for childhood cancer. Free Radic. Biol. Med. 23:870–878.

    Article  PubMed  CAS  Google Scholar 

  20. Humphris, K.M., Yoo, Y., and Szweda, L.I. (1998). Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal. Biochemistry 37:552–557.

    Article  Google Scholar 

  21. Kowaltowski, A.J. and Vercesi, A.E. (1999). Mitochondrial damage induced by conditions of oxidative stress. Free Radic. Biol. Med. 26:463–471.

    Article  PubMed  CAS  Google Scholar 

  22. Green, D.R. and Reed, J.C. (1998). Mitochondria and apoptosis. Science 281:1309–1312.

    Article  PubMed  CAS  Google Scholar 

  23. Grutter, M.G. (2000). Caspases: key players in programed cell death. Curr. Opin. Struc. Biol. 10:649–655.

    Article  CAS  Google Scholar 

  24. Zielinski, T.L., Smith, S.A., Pestka, J.J., Gray, J.I., and Smith, D.M. (2001). ELISA to quantify hexanal-protein adducts in a meat model system. J. Agric. Food Chem. 49: 3017–3023.

    Article  PubMed  CAS  Google Scholar 

  25. Smith, S.A., Pestka, J.J., Gray, J.I., and Smith, D.M. (1999). Production and specificity of polyclonal antibodies to hexanal-lysine adducts. J. Agric. Food Chem. 47: 1389–1395.

    Article  PubMed  CAS  Google Scholar 

  26. Prabhu, S.D., Chandrasekar, B., Murray, D.R., and Freeman, G.L. (1998). β-Adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling. Circulation 98:149–156.

    Google Scholar 

  27. Ping, P., Takano, H., Zhang, J., Tang, X.L., Qiu, Y., Li, R.C., et al. (1999). Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signaling mechanism for both nitric oxide-induced and ischemia-induced preconditioning. Circ. Res. 84:587–604.

    PubMed  CAS  Google Scholar 

  28. Baines, C.P., Zhang, J., Wang, G.W., Zheng, Y.T., Xiu, J.X., Cardwell, E.M., et al. (2002). Mitochondrial PKCε and MAPK form signaling modules in the murine heart: enhanced mitochondrial PKCε-MAPK interactions and differential MAPK activation in PKCε-induced cardioprotection. Circ. Res. 90:390–397.

    Article  PubMed  CAS  Google Scholar 

  29. Ghilarducci, D.P. and Tjeerdema, R.S. (1995). Fate and effects of acrolein. Rev. Environ. Contam. Toxicol. 144: 95–144.

    PubMed  CAS  Google Scholar 

  30. Laplanche, A., Clavel-Chapelon, F., Contassot, J.C., and Lanouiere, C. (1992). Exposure to vinvyl chloride monomer: results of a cohort study after a seven year follow up. The French VCM Group. Br. J. Ind. Med. 49:134–137.

    PubMed  CAS  Google Scholar 

  31. Feron, V.J., Til, H.P., de Vrijer, F., Woutersen, R.A., Cassee, F.R., and van Bladeren, P.J. (1991). Aldehydes: occurrence, carcinogenic potential, mechanism of action and risk assessment. Mutat. Res. 259:363–385.

    Article  PubMed  CAS  Google Scholar 

  32. Eder, E. and Schuler, D. (2000). An approach to cancer risk assessment for the food constituent 2-hexenal on the basis of 1, N2-propanodeoxyguanosine adducts of 2-hexenal in vivo. Arch. Toxicol. 74:642–648.

    Article  PubMed  CAS  Google Scholar 

  33. Eder, E. and Budiawan, S.D. (1999). Cancer risk assessment for crotonaldehyde and 2-hexenal: an approach. IARC Scientific Publications 150:219–232.

    PubMed  CAS  Google Scholar 

  34. Majno, G. and Joris, I. (1995). Apoptosis, oncosis, and necrosis: an overview of cell death. Am. J. Pathol. 146: 3–15.

    PubMed  CAS  Google Scholar 

  35. Narula, J., Pandey, P., Arbustini, E., Haider, N., Narula, N., Kolodgie, F.D., et al. (1999). Apoptosis in heart failure: release of cytochromec from mitochondria and activation of caspases-3 in human cardiomyopathy. Proc. Natl. Acad. Sci. USA 96:8144–8149.

    Article  PubMed  CAS  Google Scholar 

  36. Arola, O.J., Saraste, A., Pulkki, K., Kallajoki, M., Parvinen, M., and Voipio-Pulkki, L.M. (2000). Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res. 60:1789–1792.

    PubMed  CAS  Google Scholar 

  37. Sharma, K., Wang, R.X., Zhang, L.Y., Yin, D.L., Luo, X.Y., Solomon, J.C., et al. (2000). Death the Fas way: regulation and pathophysiology of CD95 and its ligand. Pharmacol. Ther. 88:333–347.

    Article  PubMed  CAS  Google Scholar 

  38. Wallach, D., Varfolomeev E.E., Malinin, N.L., Goltsev, Y.V., Kovalenko, A.V., and Boldin, M.P. (1999). Tumor necrosis factor receptor and Fas signaling mechanisms. Annu. Rev. Immunol. 17:331–367.

    Article  PubMed  CAS  Google Scholar 

  39. Condorelli, G., Roncarati, R., Ross, J., Jr., Pisani, A., Stassi, G., Todaro, M., et al. (2001). Heart-targeted overexpression of caspase-3 in mice increases infarct size and depresses cardiac function. Proc. Natl. Acad. Sci. USA 98: 9977–9982.

    Article  PubMed  CAS  Google Scholar 

  40. Laugwitz, K.L., Moretti, A., Weig, H.J., Gillitzer, A., Pinkernell, K., Ott, T., et al. (2001). Blocking caspase-activated apoptosis improves contractility in failure myocardium. Hum. Gene Ther. 12:2051–2063.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, University of Louisville, Louisville, KY

    Christopher P. Baines, Jun Zhang & Nobel C. Zong

  2. Department of Medicine, Division of Cardiology, University of Louisville, Louisville, KY

    Yan Gu, Sumanth D. Prabhu & Aruni Bhatnagar

  3. Physiology and Medicine (Cardiology), Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Suite 1609, MRL Building, 675 Charles E. Young Drive, 90095, Los Angeles, CA

    Peipei Ping, Linda L. Tsai, Ernest Cardwell, Nobel C. Zong, Thomas M. Vondriska, Paavo Korge & Guang-Wu Wang PhD

Authors
  1. Peipei Ping
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher P. Baines
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sumanth D. Prabhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Linda L. Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ernest Cardwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nobel C. Zong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thomas M. Vondriska
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Paavo Korge
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Aruni Bhatnagar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Guang-Wu Wang PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guang-Wu Wang PhD.

Additional information

Peipei Ping and Christopher P. Baines contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ping, P., Baines, C.P., Gu, Y. et al. Cardiac toxic effects of trans-2-hexenal are mediated by induction of cardiomyocyte apoptotic pathways. Cardiovasc Toxicol 3, 341–351 (2003). https://doi.org/10.1385/CT:3:4:341

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/CT:3:4:341

Key Words

Search

Navigation