Dynamic production of hypoxia-inducible factor-1alpha in early transplanted islets

• Published in: American journal of transplantation Vol. 6; no. 11; pp. 2636 - 2643
• Main Authors: Miao, G, Ostrowski, R P, Mace, J, Hough, J, Hopper, A, Peverini, R, Chinnock, R, Zhang, J, Hathout, E
• Format: Journal Article
• Language: English
• Published: United States 01.11.2006
• Subjects: Animals; Blood Glucose - metabolism; Cell Hypoxia; Diabetes Mellitus, Experimental - surgery; Glucose Tolerance Test; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Insulin - metabolism; Insulin Secretion; Islets of Langerhans Transplantation - pathology; Islets of Langerhans Transplantation - physiology; Mice; Mice, Inbred BALB C; Neovascularization, Physiologic; Subrenal Capsule Assay
• ISSN: 1600-6135

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.