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Dynamic Production of Hypoxia‐Inducible Factor‐1α in Early Transplanted Islets
Author(s) -
Miao G.,
Ostrowski R. P.,
Mace J.,
Hough J.,
Hopper A.,
Peverini R.,
Chinnock R.,
Zhang J.,
Hathout E.
Publication year - 2006
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2006.01541.x
Subject(s) - islet , medicine , transplantation , apoptosis , hypoxia (environmental) , endocrinology , point of delivery , programmed cell death , growth factor , andrology , insulin , biology , receptor , chemistry , oxygen , biochemistry , organic chemistry , agronomy
More than half of transplanted β‐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‐1α (HIF‐1α) 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‐1α‐related β‐cell death, which can be suppressed by short‐term hyperbaric oxygen therapy. On POD 7, apoptosis was not further activated by continually produced HIF‐1α. 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‐1α. We conclude that (1) transplanted islets strongly express HIF‐1α in association with β‐cell death and decreased insulin production until adequate revascularization is established and (2) early suppression of HIF‐1α results in less β‐cell death thereby minimizing early graft failure.