Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes

Rajesh Katare, Atsuhiko Oikawa, Daniela Cesselli, Antonio P. Beltrami, Elisa Avolio, Deepti Muthukrishnan, Pujika Emani Munasinghe, Gianni Angelini, Costanza Emanueli, Paolo Madeddu

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Abstract

Aims Diabetes impinges upon mechanisms of cardiovascular repair. However, the biochemical adaptation of cardiac stem cells to sustained hyperglycaemia remains largely unknown. Here, we investigate the molecular targets of high glucose-induced damage in cardiac progenitor cells (CPCs) from murine and human hearts and attempt safeguarding CPC viability and function through reactivation of the pentose phosphate pathway. Methods and results Type-1 diabetes was induced by streptozotocin. CPC abundance was determined by flow cytometry. Proliferating CPCs were identified in situ by immunostaining for the proliferation marker Ki67. Diabetic hearts showed marked reduction in CPC abundance and proliferation when compared with controls. Moreover, Sca-1pos CPCs isolated from hearts of diabetic mice displayed reduced activity of key enzymes of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD), and transketolase, increased levels of superoxide and advanced glucose end-products (AGE), and inhibition of the Akt/Pim-1/Bcl-2 signalling pathway. Similarly, culture of murine CPCs or human CD105pos progenitor cells in high glucose inhibits the pentose phosphate and pro-survival signalling pathways, leading to the activation of apoptosis. In vivo and in vitro supplementation with benfotiamine reactivates the pentose phosphate pathway and rescues CPC availability and function. This benefit is abrogated by either G6PD silencing by small interfering RNA (siRNA) or Akt inhibition by dominant-negative Akt. Conclusion We provide new evidence of the negative impact of diabetes and high glucose on mechanisms controlling CPC redox state and survival. Boosting the pentose phosphate pathway might represent a novel mechanistic target for protection of CPC integrity.

Original languageEnglish
Pages (from-to)55-65
Number of pages11
JournalCardiovascular Research
Volume97
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

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Keywords

  • Cardiac progenitor cells
  • Diabetes
  • Glucose
  • Oxidative stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Katare, R., Oikawa, A., Cesselli, D., Beltrami, A. P., Avolio, E., Muthukrishnan, D., Munasinghe, P. E., Angelini, G., Emanueli, C., & Madeddu, P. (2013). Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes. Cardiovascular Research, 97(1), 55-65. https://doi.org/10.1093/cvr/cvs291