Heme oxygenase-1 induction in islet cells results in protection from apoptosis and improved in vivo function after transplantation.
Transplantation of islets of Langerhans represents a viable therapeutic approach for the treatment of type 1 diabetes. Unfortunately, transplanted islets are susceptible to allogeneic recognition and rejection, recurrence of autoimmunity, and destruction by local inflammation at the site of implantation. The last of these phenomena might not only result in functional impairment and death of islet cells but could also contribute to amplifying the subsequent specific immune response. Induction of islet cell protection against inflammation could therefore be postulated to be a powerful means to improve overall graft fate. Heme oxygenase-1 (HO-1) has been described as an inducible protein capable of cytoprotection via radical scavenging and apoptosis prevention. The purpose of the present study was to analyze whether HO-1 upregulation in a beta-cell line and in freshly isolated murine islets could result in protection from apoptosis and improve in vivo functional performance. HO-1 upregulation was induced reproducibly with protoporphyrins and was correlated with protection from apoptosis induced in vitro with proinflammatory cytokines or Fas engagement. Furthermore, in vivo HO-1 upregulation resulted in improved islet function in a model of marginal mass islet transplantation in rodents. Strategies aimed at inducing HO-1 upregulation might result in improved success in islet transplantation.
Pileggi
A
A
Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida 33136, USA.
Molano
R D
RD
Berney
T
T
Cattan
P
P
Vizzardelli
C
C
Oliver
R
R
Fraker
C
C
Ricordi
C
C
Pastori
R L
RL
Bach
F H
FH
Inverardi
L
L
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001786:Blood Glucose / Q000378:metabolism; D004790:Enzyme Induction; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology; D012016:Reference Values; D013997:Time Factors; D014185:Transplantation, Isogeneic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation
D001786:Blood Glucose; D008565:Membrane Proteins; D011524:Protoporphyrins; D014409:Tumor Necrosis Factor-alpha; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse