title: Sumoylation of IkB attenuates NF-kB-induced nitrosative stress at rostral ventrolateral medulla and cardiovascular depression in experimental brain death.
abstract: BACKGROUND
  Small ubiquitin-related modifier (SUMO) is a group of proteins that participates in post-translational modifications. One known SUMO target is the transcription factor nuclear factor-kB (NF-kB) that plays a pivotal role in many disease processes; sumoylation inactivates NF-kB by conjugation with inhibitors of NF-kB (IkB). Our laboratory demonstrated previously that transcriptional upregulation of nitric oxide synthase II (NOS II) by NF-kB, leading to nitrosative stress by the formation of peroxynitrite in the rostral ventrolateral medulla (RVLM), underpins the defunct brain stem cardiovascular regulation that precedes brain death. Based on an experimental endotoxemia model, this study evaluated the hypothesis that sumoylation plays a pro-life role in brain death by interacting with the NF-kB/NOS II/peroxynitrite signaling pathway in the RVLM.
  
  
  RESULTS
  In Sprague-Dawley rats, intravenous administration of Escherichia coli lipopolysaccharide (LPS; 10 mg kg-1) elicited an augmentation of SUMO-1 and ubiquitin-conjugase 9 (Ubc9) mRNA or protein levels, alongside SUMO-1-conjugated proteins in the RVLM. Immunoneutralization of SUMO-1 or Ubc9 in the RVLM significantly potentiated the already diminished sumoylation of IkBα and intensified NF-kB activation and NOS II/peroxynitrite expression in this brain stem substrate, together with exacerbated fatality, cardiovascular depression and reduction of an experimental index of a life-and-death signal detected from arterial pressure that disappears in comatose patients signifying failure of brain stem cardiovascular regulation before brain death.
  
  
  CONCLUSIONS
  We conclude that sumoylation of IkB in the RVLM ameliorates the defunct brain stem cardiovascular regulation that underpins brain death in our experimental endotoxemia modal by reducing nitrosative stress via inhibition of IkB degradation that diminishes the induction of the NF-kB/NOS II/peroxynitrite signaling cascade.
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan, Republic of China.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Institute of Physiology, National Cheng Kung University, Tainan, Taiwan, Republic of China.
authors.forename: Faith C H
authors.initials: FC
authors.lastname: Li
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan, Republic of China.
authors.forename: Carol H Y
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Institute of Physiology, National Cheng Kung University, Tainan, Taiwan, Republic of China. aywchang@ncku.edu.tw.
authors.forename: Alice Y W
authors.initials: AY
authors.lastname: Chang
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan, Republic of China. shhchan@cgmh.org.tw.
authors.forename: Samuel H H
authors.initials: SH
authors.lastname: Chan
keywords: Defunct brain stem cardiovascular regulation; Nitrosative stress; Rostral ventrolateral medulla; Small ubiquitin-related modifier; Ubiquitin-conjugase 9