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

Stem Cell Reports. 2019 Mar 5;12(3):597-610. doi: 10.1016/j.stemcr.2019.01.017. Epub 2019 Feb 21.


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.

Keywords: autophagy; calpain; diabetes; endothelial dysfunction; iPSC; iPSC-ECs; ischemia-reperfusion injury; mitochondrial morphology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / drug effects*
  • Calpain / antagonists & inhibitors*
  • Cells, Cultured
  • Diabetes Complications / drug therapy*
  • Diabetes Complications / metabolism
  • Diabetes Mellitus / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Glycoproteins / pharmacology*
  • Humans
  • Hyperglycemia / drug therapy
  • Hyperglycemia / metabolism
  • Induced Pluripotent Stem Cells / drug effects*
  • Induced Pluripotent Stem Cells / metabolism
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Reactive Oxygen Species / metabolism
  • Vascular Diseases / drug therapy*
  • Vascular Diseases / metabolism


  • Glycoproteins
  • Reactive Oxygen Species
  • calpain inhibitors
  • Calpain