Nuclear Interaction between ADR-Induced p65 and p53 Mediates Cardiac Injury in iNOS (-/-) Mice

作者：Cole Marsha P^*; Tangpong Jitbanjong; Oberley Terry D; Chaiswing Luksana; Kiningham Kinsley K; Clair Daret K St

来源：PLos One, 2014, 9(2): e89251.

DOI：10.1371/journal.pone.0089251

Adriamycin (ADR) treatment causes an imbalance in the levels of nitric oxide ((NO)-N-center dot) and superoxide (O-2(center dot-)) production leading to cardiac injury. Previously we demonstrated that mice lacking inducible nitric oxide synthase (iNOS) have increased oxidative stress and mitochondrial injury. The molecular events leading to increased mitochondrial injury in iNOS deficient mice is unknown. ADR in the absence of iNOS preferentially activates a proapoptotic pathway without a concurrent increase in prosurvival pathways. Treatment with ADR leads to an increase in DNA binding activity of nuclear factor kappa B (NF kappa B) and p53 in wildtype mice. Following ADR treatment, p53, but not NF kappa B DNA binding activity, as well as the level of Bax, a p53 target gene, was increased in iNOS (-/-) mice. This apoptotic signaling effect in iNOS (-/-) is alleviated by overexpression of manganese superoxide dismutase (MnSOD). Increases in NF kappa B and p53 in ADR-treated wildtype mice did not lead to increases in target genes such as MnSOD, bcl-xL, or Bax. Moreover, co-immunoprecipitation analysis revealed that p65, a prominent member of the NF kappa B family, interacts with p53 in the nucleus. These results suggest that NF kappa B and p53 may counter act one another's actions in ADR-treated wildtype (WT) mice. Further, these results identify a novel mechanism by which oxidative stress may regulate transcription of proapoptotic genes.

• 出版日期2014-2-25