Dynamic production of hypoxia-inducible factor-1alpha in early transplanted islets.
More than half of transplanted beta-cells undergo apoptotic cell death triggered by nonimmunological factors within a few days after transplantation. To investigate the dynamic hypoxic responses in early transplanted islets, syngeneic islets were transplanted under the kidney capsule of balb/c mice. Hypoxia-inducible factor-1alpha (HIF-1alpha) was strongly expressed at post-transplant day (POD) 1, increased on POD 3, and gradually diminished on POD 14. Insulin secretion decreased on POD 3 in association with a significant increase of HIF-1alpha-related beta-cell death, which can be suppressed by short-term hyperbaric oxygen therapy. On POD 7, apoptosis was not further activated by continually produced HIF-1alpha. In contrast, improvement of nerve growth factor and duodenal homeobox factor-1 (PDx-1) production resulted in islet graft recovery and remodeling. In addition, significant activation of vascular endothelial growth factor in islet grafts on POD 7 correlated with development of massive newly formed microvessels, whose maturation is advanced on POD 14 with gradual diminution of HIF-1alpha. We conclude that (1) transplanted islets strongly express HIF-1alpha in association with beta-cell death and decreased insulin production until adequate revascularization is established and (2) early suppression of HIF-1alpha results in less beta-cell death thereby minimizing early graft failure.
Miao
G
G
Islet Transplant Laboratory, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California, USA.
Ostrowski
R P
RP
Mace
J
J
Hough
J
J
Hopper
A
A
Peverini
R
R
Chinnock
R
R
Zhang
J
J
Hathout
E
E
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015687:Cell Hypoxia; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D005951:Glucose Tolerance Test; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic; D013370:Subrenal Capsule Assay
D001786:Blood Glucose; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin