BACKGROUND: One aspect of brain death is cardiovascular deregulation because 
asystole invariably occurs shortly after its diagnosis. A suitable neural 
substrate for mechanistic delineation of this aspect of brain death resides in 
the rostral ventrolateral medulla (RVLM). RVLM is the origin of a life-and-death 
signal that our laboratory detected from blood pressure of comatose patients 
that disappears before brain death ensues. At the same time, transcriptional 
upregulation of heme oxygenase-1 in RVLM by hypoxia-inducible factor-1α (HIF-1α) 
plays a pro-life role in experimental brain death, and HIF-1α is subject to 
sumoylation activated by transient cerebral ischemia. It follows that 
sumoylation of HIF-1α in RVLM in response to hypoxia may play a modulatory role 
on brain stem cardiovascular regulation during experimental brain death.
METHODOLOGY/PRINCIPAL FINDINGS: A clinically relevant animal model that employed 
mevinphos as the experimental insult in Sprague-Dawley rat was used. Biochemical 
changes in RVLM during distinct phenotypes in systemic arterial pressure 
spectrum that reflect maintained or defunct brain stem cardiovascular regulation 
were studied. Western blot analysis, EMSA, ELISA, confocal microscopy and 
immunoprecipitation demonstrated that drastic tissue hypoxia, elevated levels of 
proteins conjugated by small ubiquitin-related modifier-1 (SUMO-1), Ubc9 (the 
only known conjugating enzyme for the sumoylation pathway) or HIF-1α, augmented 
sumoylation of HIF-1α, nucleus-bound translocation and enhanced transcriptional 
activity of HIF-1α in RVLM neurons took place preferentially during the pro-life 
phase of experimental brain death. Furthermore, loss-of-function manipulations 
by immunoneutralization of SUMO-1, Ubc9 or HIF-1α in RVLM blunted the 
upregulated nitric oxide synthase I/protein kinase G signaling cascade, which 
sustains the brain stem cardiovascular regulatory machinery during the pro-life 
phase.
CONCLUSIONS/SIGNIFICANCE: We conclude that sumoylation of HIF-1α in RVLM 
ameliorates brain stem cardiovascular regulatory failure during experimental 
brain death via upregulation of nitric oxide synthase I/protein kinase G 
signaling. This information should offer new therapeutic initiatives against 
this fatal eventuality.