Background-Heme oxygenase-1 (HO-1) is a stress-response enzyme implicated in cardioprotection. To explore whether HO-1 has a role in cardiac remodeling response, the effect of its overexpression on angiotensin II (Ang II)-induced cardiac hypertrophy was examined.
Methods and
Heme oxygenase-1 (HO-1) is an enzyme with potent immunoregulatory capacity. To evaluate the effect of HO-1 on autoimmune diabetes, female NOD mice at 9 weeks of age received a single intravenous injection of a recombinant adeno-associated virus bearing HO-1 gene (AAV-HO-1; 0.5 ؋ 10 10 -2.5 ؋ 10 10 viruses/mouse). In a dose-dependent manner, HO-1 transduction reduced destructive insulitis and the incidence of overt diabetes examined over a 15-week period. HO-1-mediated protection was associated with a lower type 1 T-helper cell (Th1)-mediated response. Adaptive transfer experiments in NOD.scid mice demonstrated that splenocytes isolated from AAV-HO-1-treated mice were less diabetogenic. Flow cytometry analysis revealed no significant difference in the percentages of CD4 ؉ CD25 ؉ regulatory T-cells between saline-treated and AAV-HO-1-treated groups. However, the CD11c ؉ major histocompatibility complex II ؉ dendritic cell population was much lower in the AAV-HO-1-treated group. A similar protective effect against diabetes was observed in NOD mice subjected to carbon monoxide (CO) gas (250 ppm CO for 2 h, twice per week). These data suggest that HO-1 slows the progression to overt diabetes in pre-diabetic NOD mice by downregulating the phenotypic maturity of dendritic cells and Th1 effector function. CO appears to mediate at least partly the beneficial effect of HO-1 in this disease setting. Diabetes 56:1240-1247, 2007 T ype 1 diabetes is a chronic autoimmune disorder characterized by the progressive destruction of pancreatic insulin-producing -cells (1). Studies on NOD mice, which spontaneously develop type 1 diabetes with features similar to the human disease, have demonstrated that the disease is initiated by infiltration of antigen-presenting cells (APCs), particularly dendritic cells, into pancreatic islets followed by recruitment of T-and B-cells (2,3). In these mice, insulitis appears around 3-4 weeks of age and is well established by 10 weeks without clinical symptoms. The progression to overt diabetes occurs in 80% of female mice by 30 weeks of age. Evidence suggests that -cell destruction is mediated primarily by a skewed type 1 T helper cell (Th1)-mediated response and the production of proinflammatory cytokines (4). How the biased Th1 phenotype and the progression to destructive insulitis are regulated over the course of type 1 diabetes development is not fully understood. Nevertheless, it is well documented that full activation of naive T-cells requires presentation of antigen in the context of the major histocompatibility complex (MHC) II complex and costimulatory signals from mature dendritic cells (5-7). Dendritic cells from NOD mice have been shown to exhibit enhanced APC function and abnormally high costimulatory and Th1-inducing abilities (8 -10). Furthermore, increasing evidence suggests that the autoimmune process is caused by the failure of immunosuppressive mechanisms (11-13). A naturally occurring CD4 ϩ CD25 ϩ regulatory T (Treg) cell population with suppressive function has been shown to ...
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