Sumoylation of Hypoxia-Inducible Factor-1α Ameliorates Failure of Brain Stem Cardiovascular Regulation in Experimental Brain Death

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.

MicroRNA-375 inhibits glioma cell proliferation and migration by downregulating RWDD3 in�vitro

“…RWDD3 is highly expressed in various tissues, such as the pituitary, cerebellum and heart, among others (5)(6)(7)(8). RWDD3 can also increase IκB levels and, like SUMO, stabilises HIF-1α during hypoxia, leading to inhibition of NF-κB and increased HIF-1 transcriptional activity (8,9). Therefore, RWDD3 may play an important role in tumour angiogenesis, growth and metastasis via the HIF-1α/VEGF pathway.…”

Nitrosative Stress-Induced Disruption of Baroreflex Neural Circuits in a Rat Model of Hepatic Encephalopathy: A DTI Study

“…In addition, the high level of glutamine-derived ammonia within mitochondria reportedly brings about generation of ROS/RNS or cerebral RNA oxidation743. It should be pointed out that previous work from our laboratory16171819202122232425 emphasizes that it is nitrosative stress induced by peroxynitrite in key nuclei of the baroreflex circuit, rather than oxidative stress, that underpins defunct baroreflex-medicated sympathetic vasomotor tone, leading to brain death. This notion is again substantiated in the present study.…”

“…Nonetheless, under pathological conditions, our laboratory has demonstrated in comatose patients that irreversible loss of baroreflex-mediated sympathetic vasomotor tone is a hallmark for brain death12131415. We further identified that nitrosative stress in key nuclei of the neural circuit is the culprit for the defunct baroreflex16 in animal models of brain death16171819202122232425. Intriguingly, patients with alcoholic cirrhosis exhibit reduced baroreflex sensitivity26, and the degree of decreased HR variability is related to the severity of HE in patients with cirrhosis27.…”

SUMO1 promotes Aβ production via the modulation of autophagy

“…8 HIF1A is subjected to sumoylation activated by transient cerebral ischemia. 9 Because HIF1A levels are correlated with BECN1/Beclin1 and LC3 expression, 10 increased HIF1A levels might serve to promote autophagy. Because SUMO modification stabilizes HIF1A, 11,12 it has been suggested that the regulation of HIF1A by SUMO influences autophagy.…”