Heme oxygenase-1 gene delivery for altering high mobility group box-1 protein in pancreatic islet

• Published in: Journal of controlled release 2022-03, Vol.343, p.326-337
• Main Authors: Kim, Min Jun, Hwang, Yong Hwa, Hwang, Jin Wook, Alam, Zahid, Lee, Dong Yun
• Format: Article
• Language: English
• Subjects: Animals; Calcineurin - metabolism; Calcineurin - pharmacology; Calcium ion; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - therapy; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Heme Oxygenase-1 - pharmacology; Histone acetyltransferase (HAT); HMGB1 Protein - genetics; HMGB1 release; Hypoxia; Islets of Langerhans; Islets of Langerhans Transplantation - methods; Mice; Pancreatic islet; Poly(ADP) ribose polymerase-1 (PARP-1); Poly(ADP-ribose) Polymerase Inhibitors
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2022.01.031

Pancreatic islet transplantation is a promising strategy for the treatment of type I diabetes. High-mobility group box-1 (HMGB1), highly expressed in islet cells, is a potent immune stimulator in immune rejection. Heme oxygenase-1 (HO1) gene therapy can modulate the release of HMGB1 by altering intracellular molecules for successful cell transplantation. After delivery of the heme oxygenase-1 (HO1) gene to islet cells using an adeno-associated viral vector (AAV), it was evaluated the changes in cytoplasmic Ca2+ ions and calcineurin activity as well as histone acetyltransferase (HAT) and Poly(ADP) ribose polymerase-1 (PARP-1). Inhibition of HMGB1 release was evaluated through altering these intracellular molecules. Then, after transplantation of HO1-transduced islets, the therapeutic effect of them was evaluated through measuring blood glucose level to diabetic mice and through immunohistochemical analysis. The transduced HO1 gene significantly inhibited HMGB1 release in islets that was under the cell damage by hypoxia exposure. It was confirmed that this result was initially due to the decrease in cytoplasmic Ca2+ ion concentration and calcineurin activity. In addition, the delivered HO1 gene simultaneously reduced the activity of HAT and PARP-1, which are involved in the translocation of HMGB1 from the nucleus to the cytoplasm. As a result, when the HO1 gene-transduced islets were transplanted into diabetic mice, the treatment efficiency of diabetes was effectively improved by increasing the survival rate of the islets. Collectively, these results suggest that HO1 gene transfer can be used for successful islet transplantation by altering the activity of intracellular signal molecules and reducing HMGB1 release. [Display omitted] •HMGB1 is a notorious trigger for inflammatory damage to cell therapy.•Adenovirally delivered HO-1 gene significantly reduces HMGB1 release from cell.•HO-1 reduces the concentration of cytoplasmic Ca2+ and calcineurin activity in the cytosol.•HO1 simultaneously reduces the activity of histone acetyltransferase (HAT) and Poly(ADP) ribose polymerase-1 (PARP-1).•HO1 gene therapy confers therapeutic effect via HMGB1 modulation.