An effective treatment for transplant-associatedarteriosclerosiswould improve the results of organ transplantation very significantly. Recent data suggest that the induced expression of heme oxygenase-1 (HO-1) before the transplant and for a short period thereafter can suppress arteriosclerosis. Similar data are available for models of atherosclerosis. HO-1is a stress responsive enzyme that catabolyzes heme into three products: the gas carbon monoxide (CO),biliverdin (which is converted to bilirubin by biliverdin reductase) and free iron (which leads to the induction of ferritin, an iron-sequestering protein). HO-1 serves as a """"""""protective"""""""" gene by virtue of its anti-inflammatory, anti-apoptotic and anti-proliferative actions. These effects can most often be substituted for by CO which inhibits the pro-inflammatory phenotype of activated monocyte/macrophages (M0)and blocks SMC proliferation. Biliverdin has similar overall effects (anti- inflammatory, anti-proliferative),although biliverdin and CO in part achieve their effects by activating different signaling cascades and impacting different components of a pathologic response. These findings show that CO and biliverdin have properties that are,or might well be, anti-atherogenic. We have shown that CO can suppress transplant-associated arteriosclerosis as well as the intimal hyperplasia seen after balloon injury, the latter also being blocked by biliverdin. Interestingly, the induced expression of HO-1or the administration of CO or biliverdin/bilirubin only to the donor leads to beneficial results when a graft is transplanted, a finding we shall investigate in the proposed studies. The overall hypothesis tested in this proposal is that expression of HO-1and subsequent generation of CO and biliverdin is part of a vascular response to injury that prevents the development of arterioscleroticlesions associated with chronic rejection of transplanted organs. In the case of CO, we have shown that its anti-inflammatory and anti-proliferative effects depend on the activation of the p38 mitogen-activated protein kinases (MARK) signal transduction pathway. As shown in Preliminary Studies, there is a relationship of biliverdin and p38 MARK as well. It thus appears that the p38 MARK signaling cascade is a major """"""""signaling switch"""""""" that regulates these functions and that modulation of this pathway dictates the protective phenotype that prevents the development of the arteriosclerotic lesion. We propose in vitro and in vivo stduies of these signaling cascades.
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| Lee, Soo Sun; Gao, Wenda; Mazzola, Silvia et al. (2007) Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells. FASEB J 21:3450-7 |
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| Goldberg, Alyssa; Parolini, Margherita; Chin, Beek Y et al. (2007) Toll-like receptor 4 suppression leads to islet allograft survival. FASEB J 21:2840-8 |
| Bach, Fritz H (2006) Carbon monoxide: from the origin of life to molecular medicine. Trends Mol Med 12:348-50 |
| Bach, Fritz H (2006) Heme oxygenase-1 and transplantation tolerance. Hum Immunol 67:430-2 |
