Subcellular localization of survivin determines its function in cardiomyocytes

Tien Jui Tsang, Ying Chang Hsueh, Erika I. Wei, David J. Lundy, Bill Cheng, You Tzung Chen, Shoei Shen Wang, Patrick C.H. Hsieh

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Rationale: Reducing cardiomyocyte death and enhancing their proliferation after myocardial infarction is perhaps the single largest challenge for cardiac tissue regeneration. Survivin (SVV) is the smallest member of the inhibitor of apoptosis (IAP) family but plays two important roles; inhibiting caspase-9 activation in the intrinsic apoptosis pathway, and regulating microtubule dynamics and chromosome segregation during cell division. Genetic depletion of cardiac SVV leads to incomplete cardiomyocyte division and abnormal heart development. However, the function of SVV in adult hearts after myocardial infarction remains unclear. Methods: A homozygous inducible cardiomyocyte-specific SVV knockout transgenic mouse model was established through crossbreeding SVVflox/flox and αMHC-MCM transgenic mice. Adult mice received consecutive intraperitoneal injection of tamoxifen to induce genetic removal of SVV in cardiomyocytes. A SVV overexpressing model was established via local delivery of SVV in wild-type mouse hearts. Results: We found that 30.82% of cardiomyocytes in the peri-infarct region of SVV knockout mice were apoptotic, significantly higher than the 22.18% in control mice. In addition, ejection fraction was 29.00±0.40% in knockout mice compared to 38.04±0.50% in control mice 21 days after myocardial infarction. On the contrary, locally overexpressing SVV in the heart improved cardiac functions. Unexpectedly, we found that altering the subcellular localization of SVV overexpression produced different outcomes. Overexpression of SVV in the cytoplasm decreased cardiomyocyte apoptosis, whereas overexpression of SVV in the nucleus enhanced cardiac regeneration. The ejection fraction of mice overexpressing SVV was 36.58±0.91%, significantly higher than 28.18± 1.70% in the GFP control group. Apoptotic cardiomyocytes were only 4.63% in mouse overexpressing cytosolic SVV, compared to 9.31% in the GFP group, and activation of caspase-3 was also reduced. Moreover, mice overexpressing NLS-SVV exhibited a better ejection fraction (36.19 ± 1.02%,) than GFP controls (26.69 ± 0.75%). NLS-SVV enhanced H3P-positive cardiomyocytes in the border zone to 0.28%, compared to only 0.08% in GFP group, through interacting with Aurora B. Conclusions: We demonstrate the importance of SVV subcellular localization in regulating post-MI cardiac repair and regeneration. We hope that this will open new translational approaches through targeted delivery of SVV.

Original languageEnglish
Pages (from-to)4577-4590
Number of pages14
JournalTheranostics
Volume7
Issue number18
DOIs
Publication statusPublished - Jan 1 2017
Externally publishedYes

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Cardiac Myocytes
Knockout Mice
Regeneration
Myocardial Infarction
Apoptosis
Transgenic Mice
Genetic Hybridization
Chromosome Segregation
Caspase 9
Tamoxifen
Intraperitoneal Injections
Microtubules
Caspase 3
Cell Division
Cytoplasm
Control Groups

Keywords

  • Cardiac regeneration
  • Myocardial infarction
  • Subcellular localization
  • Surviving

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

Cite this

Tsang, T. J., Hsueh, Y. C., Wei, E. I., Lundy, D. J., Cheng, B., Chen, Y. T., ... Hsieh, P. C. H. (2017). Subcellular localization of survivin determines its function in cardiomyocytes. Theranostics, 7(18), 4577-4590. https://doi.org/10.7150/thno.20005

Subcellular localization of survivin determines its function in cardiomyocytes. / Tsang, Tien Jui; Hsueh, Ying Chang; Wei, Erika I.; Lundy, David J.; Cheng, Bill; Chen, You Tzung; Wang, Shoei Shen; Hsieh, Patrick C.H.

In: Theranostics, Vol. 7, No. 18, 01.01.2017, p. 4577-4590.

Research output: Contribution to journalArticle

Tsang, TJ, Hsueh, YC, Wei, EI, Lundy, DJ, Cheng, B, Chen, YT, Wang, SS & Hsieh, PCH 2017, 'Subcellular localization of survivin determines its function in cardiomyocytes', Theranostics, vol. 7, no. 18, pp. 4577-4590. https://doi.org/10.7150/thno.20005
Tsang, Tien Jui ; Hsueh, Ying Chang ; Wei, Erika I. ; Lundy, David J. ; Cheng, Bill ; Chen, You Tzung ; Wang, Shoei Shen ; Hsieh, Patrick C.H. / Subcellular localization of survivin determines its function in cardiomyocytes. In: Theranostics. 2017 ; Vol. 7, No. 18. pp. 4577-4590.
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abstract = "Rationale: Reducing cardiomyocyte death and enhancing their proliferation after myocardial infarction is perhaps the single largest challenge for cardiac tissue regeneration. Survivin (SVV) is the smallest member of the inhibitor of apoptosis (IAP) family but plays two important roles; inhibiting caspase-9 activation in the intrinsic apoptosis pathway, and regulating microtubule dynamics and chromosome segregation during cell division. Genetic depletion of cardiac SVV leads to incomplete cardiomyocyte division and abnormal heart development. However, the function of SVV in adult hearts after myocardial infarction remains unclear. Methods: A homozygous inducible cardiomyocyte-specific SVV knockout transgenic mouse model was established through crossbreeding SVVflox/flox and αMHC-MCM transgenic mice. Adult mice received consecutive intraperitoneal injection of tamoxifen to induce genetic removal of SVV in cardiomyocytes. A SVV overexpressing model was established via local delivery of SVV in wild-type mouse hearts. Results: We found that 30.82{\%} of cardiomyocytes in the peri-infarct region of SVV knockout mice were apoptotic, significantly higher than the 22.18{\%} in control mice. In addition, ejection fraction was 29.00±0.40{\%} in knockout mice compared to 38.04±0.50{\%} in control mice 21 days after myocardial infarction. On the contrary, locally overexpressing SVV in the heart improved cardiac functions. Unexpectedly, we found that altering the subcellular localization of SVV overexpression produced different outcomes. Overexpression of SVV in the cytoplasm decreased cardiomyocyte apoptosis, whereas overexpression of SVV in the nucleus enhanced cardiac regeneration. The ejection fraction of mice overexpressing SVV was 36.58±0.91{\%}, significantly higher than 28.18± 1.70{\%} in the GFP control group. Apoptotic cardiomyocytes were only 4.63{\%} in mouse overexpressing cytosolic SVV, compared to 9.31{\%} in the GFP group, and activation of caspase-3 was also reduced. Moreover, mice overexpressing NLS-SVV exhibited a better ejection fraction (36.19 ± 1.02{\%},) than GFP controls (26.69 ± 0.75{\%}). NLS-SVV enhanced H3P-positive cardiomyocytes in the border zone to 0.28{\%}, compared to only 0.08{\%} in GFP group, through interacting with Aurora B. Conclusions: We demonstrate the importance of SVV subcellular localization in regulating post-MI cardiac repair and regeneration. We hope that this will open new translational approaches through targeted delivery of SVV.",
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