title: Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes.
abstract: 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.
authors.affiliation: Chair 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
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Oikawa
authors.forename: Daniela
authors.initials: D
authors.lastname: Cesselli
authors.forename: Antonio P
authors.initials: AP
authors.lastname: Beltrami
authors.forename: Elisa
authors.initials: E
authors.lastname: Avolio
authors.forename: Deepti
authors.initials: D
authors.lastname: Muthukrishnan
authors.forename: Pujika Emani
authors.initials: PE
authors.lastname: Munasinghe
authors.forename: Gianni
authors.initials: G
authors.lastname: Angelini
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000071063:Endoglin; D005434:Flow Cytometry; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010427:Pentose Phosphate Pathway / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013481:Superoxides / Q000378:metabolism; D013831:Thiamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014162:Transfection; D014174:Transketolase / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000950:Antigens, Ly; D015415:Biomarkers; D001786:Blood Glucose; C064206:ENG protein, human; D000071063:Endoglin; D017127:Glycation End Products, Advanced; D019394:Ki-67 Antigen; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D013481:Superoxides; C052617:Bcl2 protein, mouse; D005954:Glucosephosphate Dehydrogenase; D014174:Transketolase; C496636:Pim1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; D013831:Thiamine; C013835:benphothiamine