Poly (ADP-Ribose) Polymerase Inhibition Prevents Spontaneous and Recurrent Autoimmune Diabetes in NOD Mice by Inducing Apoptosis of Islet-Infiltrating Leukocytes
2003; American Diabetes Association; Volume: 52; Issue: 7 Linguagem: Inglês
10.2337/diabetes.52.7.1683
ISSN1939-327X
AutoresWilma L. Suarez‐Pinzon, Jon G. Mabley, Robert F. Power, Csaba Szabó, Alex Rabinovitch,
Tópico(s)Calcium signaling and nucleotide metabolism
ResumoPoly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. The PARP inhibitor nicotinamide prevents NAD consumption and protects islet β-cells from chemically induced necrosis but not cytokine-induced apoptosis. Therefore, it is unclear how nicotinamide protects NOD mice from autoimmune diabetes in which apoptosis is the mode of β-cell death. To investigate the mechanism of diabetes prevention by PARP inhibition, we studied the effects of a novel, potent PARP inhibitor, PJ34, a phenanthridinone derivative, on diabetes development in NOD mice and on diabetes recurrence in diabetic NOD mice transplanted with syngeneic islets. PJ34 administration from age 5 or 15 weeks significantly decreased insulitis, β-cell destruction and diabetes incidence, and protection from diabetes continued for 12 weeks after PJ34 therapy was stopped. Similarly, syngeneic islet graft survival was prolonged and outlasted therapy in PJ34-treated mice. Immunohistochemical studies revealed significantly fewer leukocytes in islet grafts of PJ34-treated mice, together with increased apoptosis of these cells and decreased expression of the T helper 1-type cytokine interferon (IFN)-γ. These results suggest that PARP inhibition protects against autoimmune β-cell destruction in NOD mice by inducing apoptosis of islet-infiltrating leukocytes and decreasing IFN-γ expression in the islets.
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