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

Rajesh Katare1, Atsuhiko Oikawa, Daniela Cesselli

  • 1Chair of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS28HW, UK. /rajesh.katare@otago.ac.nz

Cardiovascular Research
|September 22, 2012
PubMed
Abstract

Insights

Diabetes impairs cardiac stem cell repair by damaging the pentose phosphate pathway. Reactivating this pathway with benfotiamine protects cardiac progenitor cell (CPC) function and survival in diabetes.

Area of Science:

  • Cardiovascular Research
  • Stem Cell Biology
  • Metabolic Disease

Background:

  • Diabetes mellitus significantly impairs cardiovascular repair mechanisms.
  • The specific biochemical adaptations of cardiac progenitor cells (CPCs) to chronic hyperglycemia are not well understood.
  • Understanding these adaptations is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the molecular targets of high glucose-induced damage in CPCs.
  • To explore methods for safeguarding CPC viability and function in a diabetic milieu.
  • To assess the role of the pentose phosphate pathway in CPC response to hyperglycemia.

Main Methods:

  • Induction of Type-1 diabetes in murine models using streptozotocin.
  • Quantification of CPC abundance and proliferation via flow cytometry and immunostaining.
  • Analysis of pentose phosphate pathway enzyme activity, oxidative stress markers, and signaling pathways (Akt/Pim-1/Bcl-2) in CPCs.
  • In vitro culture of murine and human CPCs under high glucose conditions.
  • Intervention with benfotiamine, G6PD silencing (siRNA), and Akt inhibition.

Main Results:

  • Diabetic hearts exhibited reduced CPC abundance and proliferation.
  • Diabetic CPCs showed decreased pentose phosphate pathway activity, increased oxidative stress (superoxide, AGEs), and inhibited pro-survival signaling.
  • High glucose culture impaired CPCs by inhibiting the pentose phosphate pathway and promoting apoptosis.
  • Benfotiamine supplementation reactivated the pentose phosphate pathway, rescuing CPC availability and function.
  • The protective effects of benfotiamine were dependent on G6PD activity and Akt signaling.

Conclusions:

  • Diabetes and hyperglycemia negatively impact CPC redox state and survival mechanisms.
  • The pentose phosphate pathway is a critical mediator of CPC response to diabetic conditions.
  • Enhancing the pentose phosphate pathway presents a promising therapeutic strategy for protecting CPC integrity in diabetes.

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