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Cardiac Fas-Dependent and Mitochondria-Dependent Apoptotic Pathways in a Transgenic Mouse Model of Huntington’s Disease

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Abstract

Huntington’s disease is an autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the huntingtin gene. Heart disease is the second leading cause of death in patients with Huntington’s disease. This study was to evaluate whether cardiac Fas-dependent and mitochondria-dependent apoptotic pathways are activated in transgenic mice with Huntington’s disease. Sixteen Huntington’s disease transgenic mice (HD) and sixteen wild-type (WT) littermates were studied at 10.5 weeks of age. The cardiac characteristics, myocardial architecture, and two major apoptotic pathways in the excised left ventricle from mice were measured by histopathological analysis, Western blotting, and TUNEL assays. The whole heart weight and the left ventricular weight decreased significantly in the HD group, as compared to the WT group. Abnormal myocardial architecture, enlarged interstitial spaces, and more cardiac TUNEL-positive cells were observed in the HD group. The key components of Fas-dependent apoptosis (TNF-alpha, TNFR1, Fas ligand, Fas death receptors, FADD, activated caspase-8, and activated caspase-3) and the key components of mitochondria-dependent apoptosis (Bax, Bax-to-Bcl-2 ratio, cytosolic cytochrome c, activated caspase-9, and activated caspase-3) increased significantly in the hearts of the HD group. Cardiac Fas-dependent and mitochondria-dependent apoptotic pathways were activated in transgenic mice with Huntington’s disease, which might provide one of possible mechanisms to explain why patients with Huntington’s disease will develop heart failure.

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References

  1. Lanska, D. J., Lavine, L., Lanska, M. J., & Schoenberg, B. S. (1988). Huntington’s disease mortality in the United States. Neurology, 38, 769–772.

    Article  CAS  PubMed  Google Scholar 

  2. The Huntington’s Disease Collaborative Research Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cell 72:971–983.

    Article  Google Scholar 

  3. Perutz, M. F. (1999). Glutamine repeats and neurodegenerative diseases: Molecular aspects. Trends in Biochemical Sciences, 24, 58–63.

    Article  CAS  PubMed  Google Scholar 

  4. Chiu, E., & Alexander, L. (1982). Causes of death in Huntington’s disease. Medical Journal of Australia, 1, 153.

    CAS  PubMed  Google Scholar 

  5. Schroeder, A. M., Loh, D. H., Jordan, M. C., Roos, K. P., & Colwell, C. S. (2011). Baroreceptor reflex dysfunction in the BACHD mouse model of Huntington’s disease. PLoS Currents, 3, RRN1266.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kiriazis, H., Jennings, N. L., Davern, P., Lambert, G., Su, Y., Pang, T., et al. (2012). Neurocardiac dysregulation and neurogenic arrhythmias in a transgenic mouse model of Huntington’s disease. The Journal of Physiology, 590, 5845–5860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sathasivam, K., Hobbs, C., Turmaine, M., Mangiarini, L., Mahal, A., Bertaux, F., et al. (1999). Formation of polyglutamine inclusions in non-CNS tissue. Human Molecular Genetics, 8, 813–822.

    Article  CAS  PubMed  Google Scholar 

  8. Pattison, J. S., Sanbe, A., Maloyan, A., Osinska, H., Klevitsky, R., & Robbins, J. (2008). Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure. Circulation, 117, 2743–2751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pattison, J. S., & Robbins, J. (2008). Protein misfolding and cardiac disease: Establishing cause and effect. Autophagy, 4, 821–823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Melkani, G. C., Trujillo, A. S., Ramos, R., Bodmer, R., Bernstein, S. I., & Ocorr, K. (2013). Huntington’s disease induced cardiac amyloidosis is reversed by modulating protein folding and oxidative stress pathways in the Drosophila heart. PLoS Genetics, 9, e1004024.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wood, N. I., Sawiak, S. J., Buonincontri, G., Niu, Y., Kane, A. D., Carpenter, T. A., et al. (2012). Direct evidence of progressive cardiac dysfunction in a transgenic mouse model of Huntington’s disease. Journal of Huntington’s Disease, 1, 57–64.

    PubMed  Google Scholar 

  12. Buonincontri, G., Wood, N. I., Puttick, S. G., Ward, A. O., Carpenter, T. A., Sawiak, S. J., & Morton, A. J. (2014). Right ventricular dysfunction in the R6/2 transgenic mouse model of Huntington’s disease is unmasked by dobutamine. Journal of Huntington’s Disease, 3, 25–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Mihm, M. J., Amann, D. M., Schanbacher, B. L., Altschuld, R. A., Bauer, J. A., & Hoyt, K. R. (2007). Cardiac dysfunction in the R6/2 mouse model of Huntington’s disease. Neurobiology of Disease, 25, 297–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bishopric, N. H., Andreka, P., Slepak, T., & Webster, K. A. (2001). Molecular mechanisms of apoptosis in the cardiac myocyte. Current Opinion in Pharmacology, 1, 141–150.

    Article  CAS  PubMed  Google Scholar 

  15. Kubasiak, L. A., Hernandez, O. M., Bishopric, N. H., & Webster, K. A. (2002). Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. Proceedings of the National Academy of Sciences of the United States of America, 99, 12825–12830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Brown, G. C., & Borutaite, V. (1999). Nitric oxide, cytochrome c and mitochondria. Biochemical Society Symposia, 66, 17–25.

    Article  CAS  Google Scholar 

  17. Bang, S., Jeong, E. J., Kim, I. K., Jung, Y. K., & Kim, K. S. (2000). Fas-and tumor necrosis factor-mediated apoptosis uses the same binding surface of FADD to trigger signal transduction. A typical model for convergent signal transduction. Journal of Biological Chemistry, 275, 36217–36222.

    Article  CAS  PubMed  Google Scholar 

  18. Barnhart, B. C., Alappat, E. C., & Peter, M. E. (2003). The CD95 type I/type II model. Seminars in Immunology, 15, 185–193.

    Article  CAS  PubMed  Google Scholar 

  19. Jeremias, I., Stahnke, K., & Debatin, K. M. (2005). CD95/Apo-1/Fas: Independent cell death induced by doxorubicin in normal cultured cardiomyocytes. Cancer Immunology, Immunotherapy, 54, 655–662.

    Article  CAS  PubMed  Google Scholar 

  20. Aggarwal, B. B., Bhardwaj, U., & Takada, Y. (2004). Regulation of TRAIL-induced apoptosis by ectopic expression of antiapoptotic factors. Vitamins and Hormones, 67, 453–483.

    Article  CAS  PubMed  Google Scholar 

  21. Gross, A., Yin, X. M., Wang, K., Wei, M. C., Jockel, J., Milliman, C., et al. (1999). Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. Journal of Biological Chemistry, 274, 1156–1163.

    Article  CAS  PubMed  Google Scholar 

  22. Chiang, M. C., Chen, C. M., Lee, M. R., Chen, H. W., Chen, H. M., Wu, Y. S., et al. (2010). Modulation of energy deficiency in Huntington’s disease via activation of the peroxisome proliferator-activated receptor gamma. Human Molecular Genetics, 19, 4043–4058.

    Article  CAS  PubMed  Google Scholar 

  23. Chou, S. Y., Lee, Y. C., Chen, H. M., Chiang, M. C., Lai, H. L., Chang, H. H., et al. (2005). CGS21680 attenuates symptoms of Huntington’s disease in a transgenic mouse model. Journal of Neurochemistry, 93, 310–320.

    Article  CAS  PubMed  Google Scholar 

  24. Mielcarek, M., Inuabasi, L., Bondulich, M. K., Muller, T., Osborne, G. F., Franklin, S. A., et al. (2014). Dysfunction of the CNS-heart axis in mouse models of Huntington’s disease. PLoS Genetics, 10, e1004550.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Olmesdahl, P. J., Gregory, M. A., & Cameron, E. W. (1979). Ultrastructural artefacts in biopsied normal myocardium and their relevance to myocardial biopsy in man. Thorax, 34, 82–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bates, G. P., Mangiarini, L., Mahal, A., & Davies, S. W. (1997). Transgenic models of Huntington’s disease. Human Molecular Genetics, 6, 1633–1637.

    Article  CAS  PubMed  Google Scholar 

  27. Nagai, Y., Inui, T., Popiel, H. A., Fujikake, N., Hasegawa, K., Urade, Y., et al. (2007). A toxic monomeric conformer of the polyglutamine protein. Nature Structural and Molecular Biology, 14, 332–340.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang, Q. C., Yeh, T. L., Leyva, A., Frank, L. G., Miller, J., Kim, Y. E., et al. (2011). A compact beta model of huntingtin toxicity. The Journal of Biological Chemistry, 286, 8188–8196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Takahashi, T., Kikuchi, S., Katada, S., Nagai, Y., Nishizawa, M., & Onodera, O. (2008). Soluble polyglutamine oligomers formed prior to inclusion body formation are cytotoxic. Human Molecular Genetics, 17, 345–356.

    Article  CAS  PubMed  Google Scholar 

  30. Hsiao, H. Y., Chiu, F. L., Chen, C. M., Wu, Y. R., Chen, H. M., Chen, Y. C., et al. (2014). Inhibition of soluble tumor necrosis factor is therapeutic in Huntington’s disease. Human Molecular Genetics, 23, 4328–4344.

    Article  CAS  PubMed  Google Scholar 

  31. Luo, S., & Rubinsztein, D. C. (2009). Huntingtin promotes cell survival by preventing Pak2 cleavage. Journal of Cell Science, 122, 875–885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang, Y., Leavitt, B. R., van Raamsdonk, J. M., Dragatsis, I., Goldowitz, D., MacDonald, M. E., et al. (2006). Huntingtin inhibits caspase-3 activation. The EMBO Journal, 25, 5896–5906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shirendeb, U. P., Calkins, M. J., Manczak, M., Anekonda, V., Dufour, B., McBride, J. L., et al. (2012). Mutant huntingtin’s interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington’s disease. Human Molecular Genetics, 21, 406–420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li, S. H., Lam, S., Cheng, A. L., & Li, X. J. (2000). Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis. Human Molecular Genetics, 9, 2859–2867.

    Article  CAS  PubMed  Google Scholar 

  35. Zuccato, C., Valenza, M., & Cattaneo, E. (2010). Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiological Reviews, 90, 905–981.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Dr Yijuang Chern for offering R6/2 mice and Dr Timothy Williams for proofreading the manuscript. This study was supported by Grants from the National Science Council (NSC 100-2632-B-039-001-MY3 and NSC100-2314-B-039-016-MY) in Taiwan. This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002). Some components of the pathway diagram in the current study were modified from the Pathway Central from SABiosciences.

Conflict of interest

The authors declare no conflict of interest.

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    Authors and Affiliations

    1. Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, 91 Hsueh-Shih Road, Taichung, 40402, Taiwan

      Bor-Tsang Wu, Ching-Yi Tasi & Shin-Da Lee

    2. Department of Life Science, Fu Jen Catholic University, New Taipei City, 242, Taiwan

      Ming-Chang Chiang

    3. Laboratory of Exercise Biochemistry, Taipei Physical Education College, Taipei, Taiwan

      Chia-Hua Kuo

    4. Translational Medicine Research Center, China Medical University Hospital, Taichung, 40447, Taiwan

      Woei-Cherng Shyu

    5. Graduate Institute of Immunology, China Medical University, Taichung, 40202, Taiwan

      Woei-Cherng Shyu

    6. Department of Neurology, Center for Neuropsychiatry, China Medical University Hospital, Taichung, 40447, Taiwan

      Woei-Cherng Shyu

    7. Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan

      Chung-Lan Kao

    8. School of Medicine, National Yang-Ming University, Taipei, Taiwan

      Chung-Lan Kao

    9. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, 40202, Taiwan

      Chih-Yang Huang

    10. Institute of Medical Science, China Medical University, Taichung, 40402, Taiwan

      Chih-Yang Huang

    11. Department of Health and Nutrition Biotechnology, Asia University, Taichung, 41354, Taiwan

      Chih-Yang Huang

    12. Department of Healthcare Administration, Asia University, Taichung, 41354, Taiwan

      Shin-Da Lee

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    1. Bor-Tsang Wu
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    Correspondence to Shin-Da Lee.

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    Chih-Yang Huang and Shin-Da Lee have contributed equally to this work.

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    Wu, BT., Chiang, MC., Tasi, CY. et al. Cardiac Fas-Dependent and Mitochondria-Dependent Apoptotic Pathways in a Transgenic Mouse Model of Huntington’s Disease. Cardiovasc Toxicol 16, 111–121 (2016). https://doi.org/10.1007/s12012-015-9318-y

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    • DOI: https://doi.org/10.1007/s12012-015-9318-y

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