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Necrostatin: A Potentially Novel Cardioprotective Agent?

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Abstract

Background

Necrostatin-1 (Nec-1), a small tryptophan-based molecule, was recently reported to protect the cerebral cortex against ischemia-reperfusion (I/R) injury. We investigated the actions of Nec-1 and its so-called inactive analog, Nec-1i, in the setting of myocardial I/R injury.

Materials and methods

The actions of Nec-1 and Nec-1i were examined in cultured C2C12 and H9c2 myocytes, cardiomyocytes isolated from male Sprague–Dawley rats, Langendorff isolated perfused C57Bl/6J mouse hearts and an in vivo open-chest C57Bl/6J mouse heart model.

Results

Nec-1 at 30 μM and 100 μM (but not 100 μM Nec-1i) reduced peroxide-induced cell death in C2C12 cells from 51.2 ± 1.1% (control) to 26.3 ± 2.9% (p < 0.01 vs control) and 17.8 ± 0.9% (p < 0.001), respectively. With H9c2 cells cell death was also reduced from 73.0 ± 0.4% (control) to 56.7 ± 0% (30 μM Nec-1, p < 0.05) and 45.4 ± 3.3% (100 μM Nec-1, p < 0.01). In the isolated perfused heart Nec-1 (30 μM) reduced infarct size (calculated as a percentage of the risk area) from 48.0 ± 2.0% (control) to 32.1 ± 5.4% (p < 0.05). Nec-1i (30 μM) also reduced infarct size (32.9 ± 5.1%, p < 0.05). In anesthetized C57Bl/6J mice Nec-1 (1.65 mg/kg), given intraperitoneally to coincide with reperfusion following left anterior descending artery ligation (30 min), also reduced infarct size from 45.3 ± 5.1% (control) to 26.6 ± 4.0% (p < 0.05), whilst Nec-1i (1.74 mg/kg) was ineffective (37.8 ± 6.0%). Stimulus-induced opening of the mitochondrial permeability transition pore (MPTP) in rat cardiomyocytes, as reflected by the time until mitochondrial depolarisation, was unaffected by Nec-1 or Nec-1i at 30 μM but increased at 100 μM i.e. 91% (p < 0.05 vs control) and 152% (p < 0.001) for Nec-1 and Nec-1i, respectively.

Conclusion

This is the first study to demonstrate that necrostatins inhibit myocardial cell death and reduce infarct size, possibly via a mechanism independent of the MPTP.

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Acknowledgements

This project was supported by a Programme Grant from the British Heart Foundation.

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Authors and Affiliations

  1. The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London, WC1E 6HX, UK

    Christopher C. T. Smith, Sean M. Davidson, Shiang Y. Lim, James C. Simpkin, John S. Hothersall & Derek M. Yellon

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  1. Christopher C. T. Smith
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  2. Sean M. Davidson
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  3. Shiang Y. Lim
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  4. James C. Simpkin
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  5. John S. Hothersall
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  6. Derek M. Yellon
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Correspondence to Derek M. Yellon.

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Smith, C.C.T., Davidson, S.M., Lim, S.Y. et al. Necrostatin: A Potentially Novel Cardioprotective Agent?. Cardiovasc Drugs Ther 21, 227–233 (2007). https://doi.org/10.1007/s10557-007-6035-1

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  • DOI: https://doi.org/10.1007/s10557-007-6035-1

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