SUMO-1 delays neuronal damage in the spinal cord following ischemia/reperfusion

Jung,Hyo  Young; Kim,Dae  Won; Kwon,Hyun  Jung; Yoo,Dae  Young; Hwang,In  Koo; Won,Moo‑Ho; Cho,Tack‑Geun; Choi,Soo  Young; Moon,Seung  Myung

doi:10.3892/mmr.2017.6527

SUMO-1 delays neuronal damage in the spinal cord following ischemia/reperfusion

Authors:
- Hyo Young Jung
- Dae Won Kim
- Hyun Jung Kwon
- Dae Young Yoo
- In Koo Hwang
- Moo‑Ho Won
- Tack‑Geun Cho
- Soo Young Choi
- Seung Myung Moon
View Affiliations

Affiliations: Department of Anatomy and Cell Biology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea, Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung‑Wonju National University, Gangneung, Gangwon 25457, Republic of Korea, Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea, Department of Neurosurgery, Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul 07441, Republic of Korea, Department of Biomedical Sciences, Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Republic of Korea, Department of Neurosurgery, Dongtan Sacred Heart Hospital, College of Medicine, Hallym University, Hwaseong, Gyeonggi 18450, Republic of Korea
Published online on: April 28, 2017 https://doi.org/10.3892/mmr.2017.6527
Pages: 4312-4318

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study investigated the protective effects of small ubiquitin-like modifier 1 (SUMO-1) on spinal cord ischemic damage in rabbits. A trans‑activator of transcription (Tat)‑SUMO‑1 fusion protein was prepared, and transient spinal cord ischemia was induced by occlusion of the abdominal aorta for 15 min. Vehicle (glycerol) or 1 mg/kg Tat-1-SUMO‑1 was administered intraperitoneally to the rabbits immediately following ischemia/reperfusion. Administration of Tat-SUMO-1 did not lead to significant alterations in arterial blood gases [partial pressure (Pa)CO2 and PaO2], pH, or blood glucose levels prior to ischemia, 10 min after occlusion or 10 min after reperfusion. Mean arterial pressure was significantly decreased only during occlusion. Motor behaviors were assessed at 24, 48 and 72 h after ischemia/reperfusion using Tarlov's criteria. Administration of Tat‑SUMO‑1 significantly improved Tarlov scores 24 h after ischemia/reperfusion and the number of cresyl violet positive neurons was significantly increased in the ventral horn of the spinal cord compared with the vehicle‑treated group. However, Tarlov scores were consistently decreased at 48 and 72 h after ischemia/reperfusion in the Tat‑SUMO‑1‑treated group, and Tarlov scores and the number of cresyl violet positive neurons were not significantly different between the vehicle‑ and Tat‑SUMO‑1‑treated groups after 72 h. Tat-SUMO‑1 administration significantly ameliorated a reduction in Cu, Zn‑superoxide dismutase activity and an increase in lipid peroxidation 24 h after ischemia/reperfusion; however, these effects were not present at 72 h. These results suggested that Tat‑SUMO‑1 may delay, although not protect against, neuronal death by regulating oxidative stress in the ventral horn of the spinal cord and that combination therapy using Tat‑SUMO‑1 with other compounds may provide a therapeutic approach to decrease neuronal damage.

View Figures

View References

1	Schepens MA, Heijmen RH, Ranschaert W, Sonker U and Morshuis WJ: Thoracoabdominal aortic aneurysm repair: Results of conventional open surgery. Eur J Vasc Endovasc Surg. 37:640–645. 2009. View Article : Google Scholar
2	Cambria RP, Davison JK, Carter C, Brewster DC, Chang Y, Clark KA and Atamian S: Epidural cooling for spinal cord protection during thoracoabdominal aneurysm repair: A five-year experience. J Vasc Surg. 31:1093–1102. 2000. View Article : Google Scholar
3	Coselli JS, LeMaire SA, Köksoy C, Schmittling ZC and Curling PE: Cerebrospinal fluid drainage reduces paraplegia after thoracoabdominal aortic aneurysm repair: Results of a randomized clinical trial. J Vasc Surg. 35:631–639. 2002. View Article : Google Scholar
4	Safi HJ, Miller CC III, Huynh TT, Estrera AL, Porat EE, Winnerkvist AN, Allen BS, Hassoun HT and Moore FA: Distal aortic perfusion and cerebrospinal fluid drainage for thoracoabdominal and descending thoracic aortic repair: Ten years of organ protection. Ann Surg. 238:372–381. 2003.
5	Cimarosti H, Lindberg C, Bomholt SF, Rønn LC and Henley JM: Increased protein SUMOylation following focal cerebral ischemia. Neuropharmacology. 54:280–289. 2008. View Article : Google Scholar
6	Yang W, Sheng H, Warner DS and Paschen W: Transient focal cerebral ischemia induces a dramatic activation of small ubiquitin-like modifier conjugation. J Cereb Blood Flow Metab. 28:892–896. 2008. View Article : Google Scholar
7	Lee YJ and Hallenbeck JM: SUMO and ischemic tolerance. Neuromolecular Med. 15:771–781. 2013. View Article : Google Scholar
8	Silveirinha V, Stephens GJ and Cimarosti H: Molecular targets underlying SUMO-mediated neuroprotection in brain ischemia. J Neurochem. 127:580–591. 2013. View Article : Google Scholar
9	Wang Z, Wang R, Sheng H, Sheng SP, Paschen W and Yang W: Transient ischemia induces massive nuclear accumulation of SUMO2/3-conjugated proteins in spinal cord neurons. Spinal Cord. 51:139–143. 2013. View Article : Google Scholar
10	Yang W and Paschen W: SUMO proteomics to decipher the SUMO-modified proteome regulated by various diseases. Proteomics. 15:1181–1191. 2015. View Article : Google Scholar
11	Zhang FP, Mikkonen L, Toppari J, Palvimo JJ, Thesleff I and Jänne OA: Sumo-1 function is dispensable in normal mouse development. Mol Cell Biol. 28:5381–5390. 2008. View Article : Google Scholar :
12	Lee YJ, Mou Y, Maric D, Klimanis D, Auh S and Hallenbeck JM: Elevated global SUMOylation in Ubc9 transgenic mice protects their brains against focal cerebral ischemic damage. PLoS One. 6:e258522011. View Article : Google Scholar :
13	Hochrainer K, Jackman K, Anrather J and Iadecola C: Reperfusion rather than ischemia drives the formation of ubiquitin aggregates after middle cerebral artery occlusion. Stroke. 43:2229–2235. 2012. View Article : Google Scholar :
14	Cimarosti H, Ashikaga E, Jaafari N, Dearden L, Rubin P, Wilkinson KA and Henley JM: Enhanced SUMOylation and SENP-1 protein levels following oxygen and glucose deprivation in neurones. J Cereb Blood Flow Metab. 32:17–22. 2012. View Article : Google Scholar
15	Kilic E, Kilic U and Hermann DM: TAT fusion proteins against ischemic stroke: Current status and future perspectives. Front Biosci. 11:1716–1721. 2006. View Article : Google Scholar
16	Fonseca SB, Pereira MP and Kelley SO: Recent advances in the use of cell-penetrating peptides for medical and biological applications. Adv Drug Deliv Rev. 61:953–964. 2009. View Article : Google Scholar
17	Stalmans S, Bracke N, Wynendaele E, Gevaert B, Peremans K, Burvenich C, Polis I and De Spiegeleer B: Cell-penetrating peptides selectively cross the blood-brain barrier in vivo. PLoS One. 10:e01396522015. View Article : Google Scholar :
18	Eum WS, Kim DW, Hwang IK, Yoo KY, Kang TC, Jang SH, Choi HS, Choi SH, Kim YH, Kim SY, et al: In vivo protein transduction: Biologically active intact pep-1-superoxide dismutase fusion protein efficiently protects against ischemic insult. Free Radic Biol Med. 37:1656–1669. 2004. View Article : Google Scholar
19	Kim W, Kim DW, Jeong HJ, Yoo DY, Jung HY, Nam SM, Kim JH, Choi JH, Won MH, Yoon YS, et al: Tat-DJ-1 protects neurons from ischemic damage in the ventral horn of rabbit spinal cord via increasing antioxidant levels. Neurochem Res. 39:187–193. 2014. View Article : Google Scholar
20	DeGirolami U and Zivin JA: Neuropathology of experimental spinal cord ischemia in the rabbit. J Neuropathol Exp Neurol. 41:129–149. 1982. View Article : Google Scholar
21	Weir CJ, Zivin JA and Lyden PD: Inter-relationships between spinal cord blood flow, neuronal death and neurological function in rabbit spinal cord ischemia. Brain Res. 946:43–51. 2002. View Article : Google Scholar
22	National Research Council, . Guide for the Care and Use of Laboratory Animals. 7th. National Academy Press; Washington DC: 1996
23	Kwon HY, Eum WS, Jang HW, Kang JH, Ryu J, Lee B Ryong, Jin LH, Park J and Choi SY: Transduction of Cu, Zn-superoxide dismutase mediated by an HIV-1 Tat protein basic domain into mammalian cells. FEBS Lett. 485:163–167. 2000. View Article : Google Scholar
24	Bradford MA: A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 72:248–254. 1976. View Article : Google Scholar
25	Kiyoshima T, Fukuda S, Matsumoto M, Iida Y, Oka S, Nakakimura K and Sakabe T: Lack of evidence for apoptosis as a cause of delayed onset paraplegia after spinal cord ischemia in rabbits. Anesth Analg. 96:839–846. 2003.
26	Murakami H, Tsukube T, Kawanishi Y and Okita Y: Transcranial myogenic motor-evoked potentials after transient spinal cord ischemia predicts neurologic outcome in rabbits. J Vasc Surg. 39:207–213. 2004. View Article : Google Scholar
27	Tarlov IM: Spinal cord compression; mechanism of paralysis and treatment. Thomas CC: Springfield, Illinois: pp. 1471957
28	Jacobs TP, Kempski O, McKinley D, Dutka AJ, Hallenbeck JM and Feuerstein G: Blood flow and vascular permeability during motor dysfunction in a rabbit model of spinal cord ischemia. Stroke. 23:367–373. 1992. View Article : Google Scholar
29	Huang Y, Xie K, Li J, Xu N, Gong G, Wang G, Yu Y, Dong H and Xiong L: Beneficial effects of hydrogen gas against spinal cord ischemia-reperfusion injury in rabbits. Brain Res. 1378:125–136. 2011. View Article : Google Scholar
30	Moore WM Jr and Hollier LH: The influence of severity of spinal cord ischemia in the etiology of delayed-onset paraplegia. Ann Surg. 213:427–432. 1991. View Article : Google Scholar :
31	Wisselink W, Patetsios P, Panetta TF, Ramirez JA, Rodino W, Kirwin JD and Zikria BA: Medium molecular weight pentastarch reduces reperfusion injury by decreasing capillary leak in an animal model of spinal cord ischemia. J Vasc Surg. 27:109–116. 1998. View Article : Google Scholar
32	Shao R, Zhang FP, Tian F, Friberg P Anders, Wang X, Sjöland H and Billig H: Increase of SUMO-1 expression in response to hypoxia: Direct interaction with HIF-1alpha in adult mouse brain and heart in vivo. FEBS Lett. 569:293–300. 2004. View Article : Google Scholar
33	Saitoh H and Hinchey J: Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem. 275:6252–6258. 2000. View Article : Google Scholar
34	Lee YJ, Castri P, Bembry J, Maric D, Auh S and Hallenbeck JM: SUMOylation participates in induction of ischemic tolerance. J Neurochem. 109:257–267. 2009. View Article : Google Scholar :
35	Kho C, Lee A, Jeong D, Oh JG, Chaanine AH, Kizana E, Park WJ and Hajjar RJ: SUMO1-dependent modulation of SERCA2a in heart failure. Nature. 477:601–605. 2011. View Article : Google Scholar :
36	Tilemann L, Lee A, Ishikawa K, Aguero J, Rapti K, Santos-Gallego C, Kohlbrenner E, Fish KM, Kho C and Hajjar RJ: SUMO-1 gene transfer improves cardiac function in a large-animal model of heart failure. Sci Transl Med. 5:211ra1592013. View Article : Google Scholar
37	Bossis G and Melchior F: Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. Mol Cell. 21:349–357. 2006. View Article : Google Scholar
38	Kim W, Kim DW, Yoo DY, Chung JY, Hwang IK, Won MH, Choi SY, Jeon SW, Jeong JH, Hwang HS and Moon SM: Neuroprotective effects of PEP-1-Cu, Zn-SOD against ischemic neuronal damage in the rabbit spinal cord. Neurochem Res. 37:307–313. 2012. View Article : Google Scholar
39	Gürer B, Kertmen H, Kasim E, Yilmaz ER, Kanat BH, Sargon MF, Arikok AT, Ergüder BI and Sekerci Z: Neuroprotective effects of testosterone on ischemia/reperfusion injury of the rabbit spinal cord. Injury. 46:240–248. 2015. View Article : Google Scholar
40	Jung HY, Kim DW, Yim HS, Yoo DY, Kim JW, Won MH, Yoon YS, Choi SY and Hwang IK: Heme oxygenase-1 protects neurons from ischemic damage by upregulating expression of Cu, Zn-superoxide dismutase, catalase, and brain-derived neurotrophic factor in the rabbit spinal cord. Neurochem Res. 41:869–879. 2016. View Article : Google Scholar
41	Kim HJ, Yun J, Lee J, Hong H, Jeong J, Kim E, Bae YS and Lee KJ: SUMO1 attenuates stress-induced ROS generation by inhibiting NADPH oxidase 2. Biochem Biophys Res Commun. 410:555–562. 2011. View Article : Google Scholar
42	Pandey D, Chen F, Patel A, Wang CY, Dimitropoulou C, Patel VS, Rudic RD, Stepp DW and Fulton DJ: SUMO1 negatively regulates reactive oxygen species production from NADPH oxidases. Arterioscler Thromb Vasc Biol. 31:1634–1642. 2011. View Article : Google Scholar :
43	Guo C, Wei Q, Su Y and Dong Z: SUMOylation occurs in acute kidney injury and plays a cytoprotective role. Biochim Biophys Acta. 1852:482–489. 2015. View Article : Google Scholar
44	Huang Y, Su Z, Li Y, Zhang Q, Cui L, Su Y, Ding C, Zhang M, Feng C, Tan Y, et al: Expression and purification of glutathione transferase-small ubiquitin-related modifier-metallothionein fusion protein and its neuronal and hepatic protection against D-galactose-induced oxidative damage in mouse model. J Pharmacol Exp Ther. 329:469–478. 2009. View Article : Google Scholar