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01-12-2017 | Original Paper

The UCP2-866G/A Polymorphism Could be Considered as a Genetic Marker of Different Functional Prognosis in Ischemic Stroke After Recanalization

Authors: I. Díaz-Maroto Cicuéndez, E. Fernández-Díaz, J. García-García, J. Jordán, I. Fernández-Cadenas, J. Montaner, G. Serrano-Heras, T. Segura

Published in: NeuroMolecular Medicine | Issue 4/2017

Abstract

Recent studies based on experimental animal models of stroke have suggested that uncoupling protein 2 (UCP2), an inner mitochondrial membrane protein that is thought to regulate energy metabolism and reduce reactive oxygen species generation, provides protection against reperfusion damage. We aimed to investigate whether -866G/A polymorphism in the promoter of the UCP2 gene, which enhances its transcriptional activity, is associated with functional prognosis in patients with embolic ischemic stroke after early recanalization. We investigate a hospital-based prospective cohort of patients with acute ischemic stroke due to occlusion of the middle cerebral artery diagnosed by transcranial Doppler who obtained a partial/complete recanalization 24 h after administration of intravenous thrombolysis. The main end point of the study was functional independence defined as modified Rankin Scale 0–2 on day 90. A total of 80 patients were enrolled. The UCP2-866G/A polymorphism was determined by polymerase chain reaction–restriction fragment length polymorphism technique (14 genotype A/A (18%), 45 genotype A/G (56%) and 21 genotype G/G (26%). The percentage of patients with good functional outcome at 3 months was significantly higher in patients harboring the A/A genotype than in those with A/G or G/G genotypes (85 vs 41%, p = 0.01). The A/A genotype was found to be an independent marker of good prognosis after adjustment for secondary variables (age, sex, glucose level, NIHSS score at baseline, complete recanalization and early neurological improvement) in a logistic regression analysis (OR 0.05, 95% CI 0.01–0.48, p = 0.01). Our results suggest that the AA genotype of UCP2-866 may predict a better functional outcome in ischemic stroke after recanalization of proximal MCA occlusion.

Andrews, Z. B., Diano, S., & Horvath, T. L. (2005). Mitochondrial uncoupling proteins in the CNS: In support of function and survival. Nature Reviews Neuroscience, 6(11), 829–840.CrossRefPubMed

Arsenijevic, D., Onuma, H., Pecqueur, C., Raimbault, S., Manning, B. S., Miroux, B., et al. (2000). Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nature Genetics, 26(4), 435–439.CrossRefPubMed

Bouillaud, F., Ricquier, D., Thibault, J., & Weissenbach, J. (1985). Molecular approach to thermogenesis in brown adipose tissue: cDNA cloning of the mitochondrial uncoupling protein. Proceedings of the National Academy of Sciences, 82(2), 445–448.CrossRef

Brand, M. D., & Esteves, T. C. (2005). Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metabolism, 2(2), 85–93.CrossRefPubMed

Calabrese, V., Cornelius, C., Dinkova-Kostova, A. T., Iavicoli, I., Di Paola, R., Koverech, A., et al. (2012). Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity. Biochimica et Biophysica Acta, 1822(5), 753–783.CrossRefPubMed

Calabrese, V., Giordano, J., Signorile, A., Laura Ontario, M., Castorina, S., De Pasquale, C., et al. (2016). Major pathogenic mechanisms in vascular dementia: Roles of cellular stress response and hormesis in neuroprotection. Journal of Neuroscience Research, 94(12), 1588–1603.CrossRefPubMed

Chan, P. H. (1996). Role of oxidants in ischemic brain damage. Stroke A Journal of Cerebral Circulation, 27(6), 1124–1129.CrossRef

Dattilo, S., Mancuso, C., Koverech, G., Di Mauro, P., Ontario, M., Petralia, C. C., et al. (2015). Heat shock proteins and hormesis in the diagnosis and treatment of neurodegenerative diseases. Immunity and Ageing, 4, 12–20.

De Bilbao, F., Arsenijevic, D., Vallet, P., Hjelle, O. P., Ottersen, O. P., Bouras, C., et al. (2004). Resistance to cerebral ischemic injury in UCP2 knockout mice: Evidence for a role of UCP2 as a regulator of mitochondrial glutathione levels. Journal of Neurochemistry, 89(5), 1283–1292.CrossRefPubMed

Diano, S., Urbanski, H. F., Horvath, B., Bechmann, I., Kagiya, A., Nemeth, G., et al. (2000). Mitochondrial uncoupling protein 2 (UCP2) in the nonhuman primate brain and pituitary. Endocrinology, 141(11), 4226–4238.CrossRefPubMed

Dinkova-Kostova, A. T., Baird, L., Holmström, K. M., Meyer, C. J., & Abramov, A. Y. (2015). The spatiotemporal regulation of the Keap1-Nrf2 pathway and its importance in cellular bioenergetics. Biochemical Society Transactions, 43(4), 602–610.CrossRefPubMedPubMedCentral

Esterbauer, H., Schneitler, C., Oberkofler, H., Ebenbichler, C., Paulweber, B., Sandhofer, F., et al. (2001). A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nature Genetics, 28(2), 178–183.CrossRefPubMed

Fiskum, G., Murphy, A. N., & Beal, M. F. (1999). Mitochondria in neurodegeneration: Acute ischemia and chronic neurodegenerative diseases. Journal of Cerebral Blood Flow & Metabolism, 19(4), 351–369.CrossRef

Hacke, W., Donnan, G., Fieschi, C., Kaste, M., von Kummer, R., Broderick, J. P., et al. (2004). Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet, 363(9411), 768–774.CrossRefPubMed

Haines, B. A., Mehta, S. L., Pratt, S. M., Warden, C. H., & Li, P. A. (2010). Deletion of mitochondrial uncoupling protein-2 increases ischemic brain damage after transient focal ischemia by altering gene expression patterns and enhancing inflammatory cytokines. Journal of Cerebral Blood Flow and Metabolism, 30(11), 1825–1833.CrossRefPubMedPubMedCentral

Hidaka, S., Yoshimatsu, H., Kakuma, T., Sakino, H., Kondou, S., Hanada, R., et al. (2000). Tissue-specific expression of the uncoupling protein family in streptozotocin-induced diabetic rats. Proceedings of the Society for Experimental Biology and Medicine, 224(3), 172–177.CrossRefPubMed

Horvath, T. L., Diano, S., & Barnstable, C. (2003). Mitochondrial uncoupling protein 2 in the central nervous system: neuromodulator and neuroprotector. Biochemical Pharmacology, 65(12), 1917–1921.CrossRefPubMed

Kim-Han, J. S., & Dugan, L. L. (2005). Mitochondrial uncoupling proteins in the central nervous system. Antioxidants & Redox Signaling, 7(9–10), 1173–1181.CrossRef

Krempler, F., Esterbauer, H., Weitgasser, R., Ebenbichler, C., Patsch, J. R., Miller, K., et al. (2002). A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes, 51(11), 3331–3335.CrossRefPubMed

Kuroda, S., & Siesjö, B. K. (1997). Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. Clinical Neuroscience, 4(4), 199–212.PubMed

López-Bernardo, E., Anedda, A., Sánchez-Pérez, P., Acosta-Iborra, B., & Cadenas, S. (2015). 4-Hydroxynonenal induces Nrf2-mediated UCP3 upregulation in mouse cardiomyocytes. Free Radical Biology & Medicine, 88(Pt B), 427–438.CrossRef

Lopez-Neblina, F., Toledo, A. H., & Toledo-Pereyra, L. H. (2005). Molecular biology of apoptosis in ischemia and reperfusion. Journal of Investigative Surgery, 18(6), 335–350.CrossRefPubMed

Mattiasson, G., Shamloo, M., Gido, G., Mathi, K., Tomasevic, G., Yi, S., et al. (2003). Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nature Medicine, 9(8), 1062–1068.CrossRefPubMed

Mehta, S. L., & Li, P. A. (2009). Neuroprotective role of mitochondrial uncoupling protein 2 in cerebral stroke. Journal of Cerebral Blood Flow and Metabolism, 29(6), 1069–1078.CrossRefPubMed

Paradis, É., Clavel, S., Bouillaud, F., Ricquier, D., & Richard, D. (2003). Uncoupling protein 2: A novel player in neuroprotection. Trends in Molecular Medicine, 9(12), 522–525.CrossRefPubMed

Rha, J.-H., & Saver, J. L. (2007). The impact of recanalization on ischemic stroke outcome: A meta-analysis. Stroke, 38(3), 967–973.CrossRefPubMed

Richard, D., Clavel, S., Huang, Q., Sanchis, D., & Ricquier, D. (2001). Uncoupling protein 2 in the brain: Distribution and function. Biochemical Society Transactions, 29(Pt 6), 812–817.CrossRefPubMed

Richard, D., Rivest, R., Huang, Q., Bouillaud, F., Sanchis, D., Champigny, O., et al. (1998). Distribution of the uncoupling protein 2 mRNA in the mouse brain. Journal of Comparative Neurology, 397(4), 549–560.CrossRefPubMed

Sanderson, T. H., Reynolds, C. A., Kumar, R., Przyklenk, K., & Huttemann, M. (2013). Molecular mechanisms of ischemia-reperfusion injury in brain: Pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Molecular Neurobiology, 47(1), 9–23.CrossRefPubMed

Smith, W. S., Tsao, J. W., Billings, M. E., Johnston, S. C., Hemphill, J. C., 3rd, Bonovich, D. C., et al. (2006). Prognostic significance of angiographically confirmed large vessel intracranial occlusion in patients presenting with acute brain ischemia. Neurocritical Care, 4(1), 14–17.CrossRefPubMed

Teshima, Y., Akao, M., Jones, S. P., & Marbán, E. (2003). Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circulation Research, 93(3), 192–200.CrossRefPubMed

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. (1995). Tissue plasminogen activator for acute ischemic stroke. New England Journal of Medicine, 333(24), 1581–1587.CrossRef

Wang, Y.-X., Lee, C.-H., Tiep, S., Yu, R. T., Ham, J., Kang, H., et al. (2003). Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell, 113(2), 159–170.CrossRefPubMed

Yeo, L. L., Paliwal, P., Teoh, H. L., Seet, R. C., Chan, B. P., Wakerley, B., et al. (2013). Early and continuous neurologic improvements after intravenous thrombolysis are strong predictors of favorable long-term outcomes in acute ischemic stroke. Journal of Stroke and Cerebrovascular Diseases, 22(8), e590–e596.CrossRefPubMed

Zhang, B., Tanaka, H., & Saku, K. (2004). Simple and rapid detection of uncoupling protein-2 - 866G/A polymorphism by mutagenically separated polymerase chain reaction. Clinica Chimica Acta; International Journal of Clinical Chemistry, 344(1–2), 205–210.CrossRefPubMed

Zhang, C. Y., Baffy, G., Perret, P., Krauss, S., Peroni, O., Grujic, D., et al. (2001). Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell, 105(6), 745–755.CrossRefPubMed

Title: The UCP2-866G/A Polymorphism Could be Considered as a Genetic Marker of Different Functional Prognosis in Ischemic Stroke After Recanalization
Authors: I. Díaz-Maroto Cicuéndez
E. Fernández-Díaz
J. García-García
J. Jordán
I. Fernández-Cadenas
J. Montaner
G. Serrano-Heras
T. Segura
Publication date: 01-12-2017
Publisher: Springer US
Published in: NeuroMolecular Medicine / Issue 4/2017
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-017-8470-x

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Springer Medicine

The UCP2-866G/A Polymorphism Could be Considered as a Genetic Marker of Different Functional Prognosis in Ischemic Stroke After Recanalization

Abstract

ACC 2024 Congress

Springer Medicine

Abstract

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