Heme Oxygenase-1 Induction in Islet Cells Results in Protection From Apoptosis and Improved In Vivo Function After Transplantation

Abstract

1Transplantation 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. T ype 1 diabetes results from the autoimmune destruction of pancreatic ␤-cells (1). Conventional therapy, based on the administration of exogenous insulin, often is characterized by the occurrence of systemic complications, including angiopathy and neuropathy. Improvement in metabolic control, through intensive insulin therapy, results in decreased incidence and progression of complications, but it is often associated with the occurrence of severe hypoglycemic episodes (2). Conversely, transplantation of islets of Langerhans, when successful, is characterized by excellent metabolic control in the absence of hypoglycemia (3).Transplanted islets are susceptible not only to rejection and recurrence of autoimmunity but also to damage mediated by nonspecific inflammatory events that occur in the microenvironment early after transplantation. Early inflammation at the site of implantation leads to generation and release of biological mediators, such as cytokines and oxygen radicals that can damage islet cells, inducing either functional impairment or death (4 -8). Islet ␤-cells are in fact exquisitely sensitive to the noxious effects of selected proinflammatory mediators and oxidative stress (9 -11). Inflammation can not only functionally impair or reduce the mass of implanted islets but can also result in the amplification of the subsequent immune response in a transplantation setting. In the transplanted islets, the induction of cytoprotective genes that are capable of scavenging oxygen radicals and preventing the toxic effects of proinflammatory cytokines might therefore promote early function (12-16).Heme oxygenase-1 (HO-1) has been identified as a ubiquitous stress protein induced in many cell types by various stimulants, such as hemolysis, inflammatory cytokines, oxidative stress, heat shock, heavy metals, and endotoxin (17)(18)(19)(20)(21)(22). HO-1 is the rate-limiting enzyme in the heme degradative pathway that catalyzes the oxidation of heme into biliverdin, carbon monoxide (CO), and free iron (23). Biliverdin is readily converted by biliverdin reductase into the bile pigment bilirubin, a powerful antioxidant (24), and free iron stimulates the production of ferritin. Induction of HO-1 results in protection from cytokine-induced apoptosis and oxidative stress in selected in vitro and in vivo models (25-28). The current working hypothesis on the mechanisms of action of HO-1 suggests that, in add...

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

“…Soares et al (1998) first demonstrated that the overexpression of HO-1 prevents apoptosis in ECs. This was subsequently confirmed in numerous other cell types in response to a wide spectrum of apoptotic stimuli Brouard et al, 2000;Petrache et al, 2000;Shiraishi et al, 2000;Pileggi et al, 2001). The antiapoptotic effect of HO-1 is reversed in the presence of HO-1 inhibitors or in cells overexpressing antisense HO-1 (Petrache et al, 2000).…”

High glucose and hydrogen peroxide increase c-Myc and haeme-oxygenase 1 mRNA levels in rat pancreatic islets without activating NF?B

“…Comparable results were obtained with both methods in insulin-producing RINm5 cells exposed to IL-1β for 30 min. Moreover, the signal intensity of NFκB activation detected by the ELISA kit was proportional to the number of IL-1β-treated cells in RINm5 cells, INS-1 cells and primary beta cells (25,50 and 100×10 3 cells) (data not shown).…”

“…Among the genes induced by IL-1β and supraphysiological glucose concentrations, the transcription factor c-Myc stimulates apoptosis more than proliferation in rodent beta cells [21][22][23], whereas the antioxidant enzyme haeme-oxygenase 1 (HO1) improves beta cell survival under various stressful conditions [17,[24][25][26]. In vitro, overnight culture of rat islets in the presence of 30 mmol/l glucose (G30) instead of 10 mmol/l glucose (G10) markedly stimulated expression of HO1 and c-Myc at the mRNA and protein levels in a Ca 2+ -and cyclic AMP-dependent manner without affecting c-Myc or HO1 mRNA stability [27,28].…”

Inhibition of c-jun N terminal kinase (JNK) improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3 (GSK-3) phosphorylation

“…Islets (either 2,000, 1,000 or 500 IEQ per mouse) were transplanted in the kidney subcapsular space of diabetic Nu/Nu mice under general anaesthesia [26,27]. Subsequent experiments, where both islets and recipients were treated with L-JNKI (2 h before transplantation and daily for the following 15 days), were performed with an islet mass of 1,000 IEQ.…”