Interdiction of the Diabetic State in NOD Mice by Sustained Induction of Heme Oxygenase: Possible Role of Carbon Monoxide and Bilirubin

Abstract

The aims of the present study were to assess whether sustained HO-1 expression could moderate or prevent diabetes in an animal model of the disease and, if so, to examine the possible mechanisms involved. Our results showed that HO-1 expression and HO activity were upregulated in the pancreas of non-obese diabetic (NOD) mice by the weekly administration of cobalt protoporphyrin (CoPP). Blood glucose levels in CoPPtreated mice decreased to normal, but continuously increased in untreated controls. Beta-cell numbers were preserved in the islets of CoPP-treated mice, whereas no beta cells were found in untreated diabetic mice. The number of CD11c(+) dendritic cells was significantly decreased in the pancreas of CoPP-treated NOD mice, but this effect was reversed by the inhibition of HO activity. Increased levels of HO-1 produced a new pancreatic phenotype, as reflected by increases in phosphorylated AKT, BcL-xL and RSK levels, and decreases in O(2)- and 3-NT levels. These novel findings provide a link between the increase in HO-1 activity, with its concurrent enhanced production of carbon monoxide (CO) and bilirubin, a decrease in infiltrated CD11c(+) dendritic cells and an increase in anti-apoptotic proteins, including RSK and BcL-xL, in the interdiction of the diabetic state.

Carbon Monoxide Inhibits TLR-Induced Dendritic Cell Immunogenicity

“…Previously published data described that overexpression of HO-1 or in vivo systemic CO treatment attenuated the progression of diabetes in spontaneously autoimmune diabetic NOD mice (10,11). These results and ours in the model of induced autoimmune diabetes support the use of ex vivo CO-treated DCs loaded with ␤ cell autoantigens to induce tolerance in NOD mice.…”

Hyperbilirubinemia Reduces the Streptozotocin-Induced Pancreatic Damage through Attenuating the Oxidative Stress in the Gunn Rat

“…In type 2 diabetic animals, NOX2 and p22phox were significantly increased in the pancreas islets and angiotensin II type 1 receptor agonist attenuated the increased expression and partially restored the decreased insulin contents in islets (Nakayama et al 2005). In the early phase of diabetes in NOD mice, the upregulation of heme oxygenase-1, a key enzyme in bilirubin production, delayed the development of diabetes by decreasing p47phox and superoxide generation and increasing antiapoptotic signaling protein (Li et al 2007). We confirmed that the STZ-induced pancreas destruction in the Wistar rats was associated with increased expressions of NOX4, p22phox, and p67phox, and an increased level of H 2 O 2 , which were attenuated in the Gunn rats.…”

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

“…In NOD mice, transient and systemic overexpression of mHo-1 by viral transduction or using CoPP induction can successfully reduce the degree of insulitis and decrease the frequency of spontaneous diabetes because both systemic autoimmunity and ROS production by the pancreas are suppressed [14,30]. However, it is unclear whether constitutive production of HO-1 in a beta cell-specific manner could prevent autoimmune diabetes and prolong graft survival following syngeneic islet transplantation.…”