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Abstract
BackgroundOne 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 FindingsA 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/SignificanceWe 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.
Highlights
As much as brain death is currently the legal definition of death in the United States [1], European Union [2] or Taiwan [3] and is of paramount clinical importance, its cellular and molecular underpinning remains relatively unsettled
We further demonstrated that nitric oxide (NO) generated by NO synthase I (NOS I) in rostral ventrolateral medulla (RVLM), followed by activation of the soluble guanylyl cyclase/cGMP/ protein kinase G (PKG) cascade, is responsible for the pro-life phase; peroxynitrite formed by a reaction between NOS II-derived NO and superoxide anion underlies the prodeath phase [13,14]
Sumoylation of proteins in RVLM ameliorates failure of brain stem cardiovascular regulation associated with experimental brain death
Summary
As much as brain death is currently the legal definition of death in the United States [1], European Union [2] or Taiwan [3] and is of paramount clinical importance, its cellular and molecular underpinning remains relatively unsettled. The power density of the LF component undergoes a dramatic reduction or loss before brain death ensues in comatose patients [5,6,7] That this life-anddeath signal originates from the rostral ventrolateral medulla (RVLM) [8], which is known classically for its role in tonic maintenance of vasomotor tone and SAP [9], allows this brain stem site to be a suitable neural substrate for mechanistic assessment of the brain stem cardiovascular regulatory functions associated with brain death [10]. Transcriptional upregulation of heme oxygenase-1 in RVLM by hypoxia-inducible factor-1a (HIF-1a) plays a pro-life role in experimental brain death, and HIF-1a is subject to sumoylation activated by transient cerebral ischemia. It follows that sumoylation of HIF-1a in RVLM in response to hypoxia may play a modulatory role on brain stem cardiovascular regulation during experimental brain death
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