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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

53 Citations (Scopus)


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.

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-1(pos) 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 CD105(pos) 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.

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
Article number97
Pages (from-to)55-65
Number of pages11
JournalCardiovascular Research
Issue number1
Publication statusPublished - 1 Jan 2013

Structured keywords

  • Centre for Surgical Research


  • Animals
  • Antigens, CD
  • Antigens, Ly
  • Apoptosis
  • Biological Markers
  • Blood Glucose
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Diabetes Mellitus, Experimental
  • Diabetes Mellitus, Type 1
  • Flow Cytometry
  • Glucosephosphate Dehydrogenase
  • Glycosylation End Products, Advanced
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen
  • Male
  • Membrane Proteins
  • Mice
  • Myocytes, Cardiac
  • Oxidative Stress
  • Pentose Phosphate Pathway
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-pim-1
  • RNA Interference
  • Receptors, Cell Surface
  • Signal Transduction
  • Stem Cells
  • Superoxides
  • Thiamine
  • Transfection
  • Transketolase


Dive into the research topics of 'Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes'. Together they form a unique fingerprint.

Cite this