Skip to main content
Erschienen in: NeuroMolecular Medicine 4/2017

17.10.2017 | Original Paper

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

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

Erschienen in: NeuroMolecular Medicine | Ausgabe 4/2017

Einloggen, um Zugang zu erhalten

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.
Literatur
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat Brand, M. D., & Esteves, T. C. (2005). Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metabolism, 2(2), 85–93.CrossRefPubMed Brand, M. D., & Esteves, T. C. (2005). Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metabolism, 2(2), 85–93.CrossRefPubMed
Zurück zum Zitat 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., 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
Zurück zum Zitat 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 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
Zurück zum Zitat Chan, P. H. (1996). Role of oxidants in ischemic brain damage. Stroke A Journal of Cerebral Circulation, 27(6), 1124–1129.CrossRef Chan, P. H. (1996). Role of oxidants in ischemic brain damage. Stroke A Journal of Cerebral Circulation, 27(6), 1124–1129.CrossRef
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat Kuroda, S., & Siesjö, B. K. (1997). Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. Clinical Neuroscience, 4(4), 199–212.PubMed Kuroda, S., & Siesjö, B. K. (1997). Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. Clinical Neuroscience, 4(4), 199–212.PubMed
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat Rha, J.-H., & Saver, J. L. (2007). The impact of recanalization on ischemic stroke outcome: A meta-analysis. Stroke, 38(3), 967–973.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
Zurück zum Zitat 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., 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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 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
Zurück zum Zitat 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, 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
Zurück zum Zitat 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 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
Metadaten
Titel
The UCP2-866G/A Polymorphism Could be Considered as a Genetic Marker of Different Functional Prognosis in Ischemic Stroke After Recanalization
verfasst von
I. Díaz-Maroto Cicuéndez
E. Fernández-Díaz
J. García-García
J. Jordán
I. Fernández-Cadenas
J. Montaner
G. Serrano-Heras
T. Segura
Publikationsdatum
17.10.2017
Verlag
Springer US
Erschienen in
NeuroMolecular Medicine / Ausgabe 4/2017
Print ISSN: 1535-1084
Elektronische ISSN: 1559-1174
DOI
https://doi.org/10.1007/s12017-017-8470-x

Weitere Artikel der Ausgabe 4/2017

NeuroMolecular Medicine 4/2017 Zur Ausgabe

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Neu im Fachgebiet Neurologie

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.