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

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

Author information

1
Signature Research Program in Cardiovascular & Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore.
2
Department of Basic Medical Sciences, University of Arizona, Phoenix, AZ 85004, USA.
3
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Signature Research Program in Cardiovascular & Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore; Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, 50603 Kuala Lumpur, Malaysia.
5
Department of Pharmacology, The University of Illinois College of Medicine, Chicago, IL 60612, USA.
6
Department of Pharmacology, The University of Illinois College of Medicine, Chicago, IL 60612, USA; Division of Cardiology, Department of Medicine, The University of Illinois College of Medicine, 909 S Wolcott Avenue, Chicago, IL 60612, USA.
7
Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan.
8
Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351 Republic of Korea. Electronic address: shinehr@skku.edu.
9
Department of Pharmacology, The University of Illinois College of Medicine, Chicago, IL 60612, USA; Division of Cardiology, Department of Medicine, The University of Illinois College of Medicine, 909 S Wolcott Avenue, Chicago, IL 60612, USA. Electronic address: sangging@uic.edu.

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.

KEYWORDS:

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

PMID:
30799273
DOI:
10.1016/j.stemcr.2019.01.017
Free PMC Article

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