Nogo-A knockdown inhibits hypoxia/reoxygenation-induced activation of mitochondrial-dependent apoptosis in cardiomyocytes

J. P. Sarkey, M. Chu, M. McShane, E. Bovo, Y. Ait Mou, A. V. Zima, P. P. de Tombe, G. L. Kartje, J. L. Martin

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Abstract

Programmed cell death of cardiomyocytes following myocardial ischemia increases biomechanical stress on the remaining myocardium, leading to myocardial dysfunction that may result in congestive heart failure or sudden death. Nogo-A is well characterized as a potent inhibitor of axonal regeneration and plasticity in the central nervous system, however, the role of Nogo-A in non-nervous tissues is essentially unknown. In this study, Nogo-A expression was shown to be significantly increased in cardiac tissue from patients with dilated cardiomyopathy and from patients who have experienced an ischemic event. Nogo-A expression was clearly associated with cardiomyocytes in culture and was localized predominantly in the endoplasmic reticulum. In agreement with the findings from human tissue, Nogo-A expression was significantly increased in cultured neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation. Knockdown of Nogo-A in cardiomyocytes markedly attenuated hypoxia/reoxygenation-induced apoptosis, as indicated by the significant reduction of DNA fragmentation, phosphatidylserine translocation, and caspase-3 cleavage, by a mechanism involving the preservation of mitochondrial membrane potential, the inhibition of ROS accumulation, and the improvement of intracellular calcium regulation. Together, these data demonstrate that knockdown of Nogo-A may serve as a novel therapeutic strategy to prevent the loss of cardiomyocytes following ischemic/hypoxic injury.

Original languageEnglish
Pages (from-to)1044-1055
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume50
Issue number6
DOIs
Publication statusPublished - 1 Jun 2011
Externally publishedYes

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Keywords

  • Cell death
  • Ischemic cardiomyopathy
  • Myocardial infarction
  • Reticulon-4A
  • Sarcoplasmic/endoplasmic reticulum

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Sarkey, J. P., Chu, M., McShane, M., Bovo, E., Mou, Y. A., Zima, A. V., de Tombe, P. P., Kartje, G. L., & Martin, J. L. (2011). Nogo-A knockdown inhibits hypoxia/reoxygenation-induced activation of mitochondrial-dependent apoptosis in cardiomyocytes. Journal of Molecular and Cellular Cardiology, 50(6), 1044-1055. https://doi.org/10.1016/j.yjmcc.2011.03.004