Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy

Sang Bing Ong, Won Hee Lee, Ning Yi Shao, Nur Izzah Ismail, Khairunnisa Katwadi, Mim Mim Lim, Xiu Yi Kwek, Nathaly Anto Michel, Jiajun Li, Jordan Newson, Soroush Tahmasebi, Jalees Rehman, Kazuki Kodo, Hye Ryoun Jang, Sang Ging Ong

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The relationship between diabetes and endothelial dysfunction remains unclear, particularly the association with pathological activation of calpain, an intracellular cysteine protease. Here, we used human induced pluripotent stem cells-derived endothelial cells (iPSC-ECs) to investigate the effects of diabetes on vascular health. Our results indicate that iPSC-ECs exposed to hyperglycemia had impaired autophagy, increased mitochondria fragmentation, and was associated with increased calpain activity. In addition, hyperglycemic iPSC-ECs had increased susceptibility to cell death when subjected to a secondary insult—simulated ischemia-reperfusion injury (sIRI). Importantly, calpain inhibition restored autophagy and reduced mitochondrial fragmentation, concurrent with maintenance of ATP production, normalized reactive oxygen species levels and reduced susceptibility to sIRI. Using a human iPSC model of diabetic endotheliopathy, we demonstrated that restoration of autophagy and prevention of mitochondrial fragmentation via calpain inhibition improves vascular integrity. Our human iPSC-EC model thus represents a valuable platform to explore biological mechanisms and new treatments for diabetes-induced endothelial dysfunction.

Original languageEnglish
Pages (from-to)597-610
Number of pages14
JournalStem cell reports
Volume12
Issue number3
DOIs
Publication statusPublished - 2019 Mar 5

Keywords

  • autophagy
  • calpain
  • diabetes
  • endothelial dysfunction
  • iPSC
  • iPSC-ECs
  • ischemia-reperfusion injury
  • mitochondrial morphology

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Ong, S. B., Lee, W. H., Shao, N. Y., Ismail, N. I., Katwadi, K., Lim, M. M., Kwek, X. Y., Michel, N. A., Li, J., Newson, J., Tahmasebi, S., Rehman, J., Kodo, K., Jang, H. R., & Ong, S. G. (2019). Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy. Stem cell reports, 12(3), 597-610. https://doi.org/10.1016/j.stemcr.2019.01.017