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Current Neuropharmacology

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ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

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Review Article

Uncoupling Protein 2 as a Pathogenic Determinant and Therapeutic Target in Cardiovascular and Metabolic Diseases

Author(s): Rosita Stanzione*, Maurizio Forte, Maria Cotugno, Franca Bianchi, Simona Marchitti, Carla Letizia Busceti, Francesco Fornai and Speranza Rubattu*

Volume 20, Issue 4, 2022

Published on: 24 February, 2022

Page: [662 - 674] Pages: 13

DOI: 10.2174/1570159X19666210421094204

Price: $65

Open Access Journals Promotions 2
Abstract

Uncoupling protein 2 (UCP2) is a mitochondrial protein that acts as an anion carrier. It is involved in the regulation of several processes, including mitochondrial membrane potential, generation of reactive oxygen species within the inner mitochondrial membrane and calcium homeostasis. UCP2 expression can be regulated at different levels: genetic (gene variants), transcriptional [by peroxisome proliferator-activated receptors (PPARs) and microRNAs], and post-translational. Experimental evidence indicates that activation of UCP2 expression through the AMPK/PPAR-α axis exerts a protective effect toward renal damage and stroke occurrence in an animal model of ischemic stroke (IS) associated with hypertension. UCP2 plays a key role in heart diseases (myocardial infarction and cardiac hypertrophy) and metabolic disorders (obesity and diabetes). In humans, UCP2 genetic variants (-866G/A and Ala55Val) associate with an increased risk of type 2 diabetes mellitus and IS development. Over the last few years, many agents that modulate UCP2 expression have been identified. Some of them are natural compounds of plant origin, such as Brassica oleracea, curcumin, berberine and resveratrol. Other molecules, currently used in clinical practice, include anti-diabetic (gliptin) and chemotherapeutic (doxorubicin and taxol) drugs. This evidence highlights the relevant role of UCP2 for the treatment of a wide range of diseases, which affect the national health systems of Western countries. We will review current knowledge on the physiological and pathological implications of UCP2 with particular regard to cardiovascular and metabolic disorders and will focus on the available therapeutic approaches affecting UCP2 level for the treatment of human diseases.

Keywords: UCP2, stroke, cardiovascular disease, diabetes, obesity, therapeutics.

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[1]
Nedergaard, J.; Ricquier, D.; Kozak, L.P. Uncoupling proteins: current status and therapeutic prospects. EMBO Rep., 2005, 6(10), 917-921.
[http://dx.doi.org/10.1038/sj.embor.7400532] [PMID: 16179945]
[2]
Rousset, S.; Alves-Guerra, M.C.; Mozo, J.; Miroux, B.; Cassard-Doulcier, A.M.; Bouillaud, F.; Ricquier, D. The biology of mitochondrial uncoupling proteins. Diabetes, 2004, 53(Suppl. 1), S130-S135.
[http://dx.doi.org/10.2337/diabetes.53.2007.S130] [PMID: 14749278]
[3]
Nicholls, D.G. A history of UCP1. Biochem. Soc. Trans., 2001, 29(Pt 6), 751-755.
[http://dx.doi.org/10.1042/bst0290751] [PMID: 11709069]
[4]
Nicholls, D.G.; Locke, R.M. Thermogenic mechanisms in brown fat. Physiol. Rev., 1984, 64(1), 1-64.
[http://dx.doi.org/10.1152/physrev.1984.64.1.1] [PMID: 6320232]
[5]
Feldmann, H.M.; Golozoubova, V.; Cannon, B.; Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab., 2009, 9(2), 203-209.
[http://dx.doi.org/10.1016/j.cmet.2008.12.014] [PMID: 19187776]
[6]
Bouillaud, F.; Couplan, E.; Pecqueur, C.; Ricquier, D. Homologues of the uncoupling protein from brown adipose tissue (UCP1): UCP2, UCP3, BMCP1 and UCP4. Biochim. Biophys. Acta, 2001, 1504(1), 107-119.
[http://dx.doi.org/10.1016/S0005-2728(00)00241-3] [PMID: 11239488]
[7]
Erlanson-Albertsson, C. Uncoupling proteins--a new family of proteins with unknown function. Nutr. Neurosci., 2002, 5(1), 1-11.
[http://dx.doi.org/10.1080/10284150290007038] [PMID: 11929192]
[8]
Gaudry, M.J.; Jastroch, M. Molecular evolution of uncoupling proteins and implications for brain function. Neurosci. Lett., 2019, 696, 140-145.
[http://dx.doi.org/10.1016/j.neulet.2018.12.027] [PMID: 30582970]
[9]
Mailloux, R.J.; Harper, M.E. Uncoupling proteins and the control of mitochondrial reactive oxygen species production. Free Radic. Biol. Med., 2011, 51(6), 1106-1115.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.06.022] [PMID: 21762777]
[10]
Brand, M.D.; Esteves, T.C. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab., 2005, 2(2), 85-93.
[http://dx.doi.org/10.1016/j.cmet.2005.06.002] [PMID: 16098826]
[11]
Tian, X.Y.; Ma, S.; Tse, G.; Wong, W.T.; Huang, Y. Uncoupling protein 2 in cardiovascular health and disease. Front. Physiol., 2018, 9, 1060.
[http://dx.doi.org/10.3389/fphys.2018.01060] [PMID: 30116205]
[12]
Lan, C.; Chen, X.; Zhang, Y.; Wang, W.; Wang, W.E.; Liu, Y.; Cai, Y.; Ren, H.; Zheng, S.; Zhou, L.; Zeng, C. Curcumin prevents strokes in stroke-prone spontaneously hypertensive rats by improving vascular endothelial function. BMC Cardiovasc. Disord., 2018, 18(1), 43.
[http://dx.doi.org/10.1186/s12872-018-0768-6] [PMID: 29490624]
[13]
Pierelli, G.; Stanzione, R.; Forte, M.; Migliarino, S.; Perelli, M.; Volpe, M.; Rubattu, S. Uncoupling Protein 2: a key player and a potential therapeutic target in vascular diseases. Oxid. Med. Cell. Longev., 2017, 2017 ,7348372.
[http://dx.doi.org/10.1155/2017/7348372] [PMID: 29163755]
[14]
Busceti, C.L.; Cotugno, M.; Bianchi, F.; Forte, M.; Stanzione, R.; Marchitti, S.; Battaglia, G.; Nicoletti, F.; Fornai, F.; Rubattu, S. Brain overexpression of uncoupling protein-2 (UCP2) delays renal damage and stroke occurrence in stroke-prone spontaneously hypertensive rats. Int. J. Mol. Sci., 2020, 21(12) ,E4289.
[http://dx.doi.org/10.3390/ijms21124289] [PMID: 32560241]
[15]
Hidaka, S.; Kakuma, T.; Yoshimatsu, H.; Yasunaga, S.; Kurokawa, M.; Sakata, T. Molecular cloning of rat uncoupling protein 2 cDNA and its expression in genetically obese Zucker fatty (fa/fa) rats. Biochim. Biophys. Acta, 1998, 1389(3), 178-186.
[http://dx.doi.org/10.1016/S0005-2760(97)00188-4] [PMID: 9512646]
[16]
Thompson, M.P.; Kim, D. Links between fatty acids and expression of UCP2 and UCP3 mRNAs. FEBS Lett., 2004, 568(1-3), 4-9.
[http://dx.doi.org/10.1016/j.febslet.2004.05.011] [PMID: 15196910]
[17]
Mattiasson, G.; Sullivan, P.G. The emerging functions of UCP2 in health, disease, and therapeutics. Antioxid. Redox Signal., 2006, 8(1-2), 1-38.
[http://dx.doi.org/10.1089/ars.2006.8.1] [PMID: 16487034]
[18]
Cadenas, S. Mitochondrial uncoupling, ROS generation and cardioprotection. Biochim. Biophys. Acta Bioenerg., 2018, 1859(9), 940-950.
[http://dx.doi.org/10.1016/j.bbabio.2018.05.019] [PMID: 29859845]
[19]
Brand, M.D.; Chien, L.F.; Ainscow, E.K.; Rolfe, D.F.; Porter, R.K. The causes and functions of mitochondrial proton leak. Biochim. Biophys. Acta, 1994, 1187(2), 132-139.
[http://dx.doi.org/10.1016/0005-2728(94)90099-X] [PMID: 8075107]
[20]
Suski, J.; Lebiedzinska, M.; Bonora, M.; Pinton, P.; Duszynski, J.; Wieckowski, M.R. Relation between mitochondrial membrane potential and ROS formation. Methods Mol. Biol., 2018, 1782, 357-381.
[http://dx.doi.org/10.1007/978-1-4939-7831-1_22] [PMID: 29851012]
[21]
Zhao, R.Z.; Jiang, S.; Zhang, L.; Yu, Z.B. Mitochondrial electron transport chain, ROS generation and uncoupling.(Review). Int. J. Mol. Med., 2019, 44(1), 3-15.
[http://dx.doi.org/10.3892/ijmm.2019.4188] [PMID: 31115493]
[22]
Joseph, J.W.; Koshkin, V.; Saleh, M.C.; Sivitz, W.I.; Zhang, C.Y.; Lowell, B.B.; Chan, C.B.; Wheeler, M.B. Free fatty acid-induced beta-cell defects are dependent on uncoupling protein 2 expression. J. Biol. Chem., 2004, 279(49), 51049-51056.
[http://dx.doi.org/10.1074/jbc.M409189200] [PMID: 15448158]
[23]
Zhang, C.Y.; Baffy, G.; Perret, P.; Krauss, S.; Peroni, O.; Grujic, D.; Hagen, T.; Vidal-Puig, A.J.; Boss, O.; Kim, Y.B.; Zheng, X.X.; Wheeler, M.B.; Shulman, G.I.; Chan, C.B.; Lowell, B.B. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell, 2001, 105(6), 745-755.
[http://dx.doi.org/10.1016/S0092-8674(01)00378-6] [PMID: 11440717]
[24]
Pecqueur, C.; Alves-Guerra, C.; Ricquier, D.; Bouillaud, F. UCP2, a metabolic sensor coupling glucose oxidation to mitochondrial metabolism? IUBMB Life, 2009, 61(7), 762-767.
[http://dx.doi.org/10.1002/iub.188] [PMID: 19514063]
[25]
Cadenas, E.; Davies, K.J. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic. Biol. Med., 2000, 29(3-4), 222-230.
[http://dx.doi.org/10.1016/S0891-5849(00)00317-8] [PMID: 11035250]
[26]
Arsenijevic, D.; Onuma, H.; Pecqueur, C.; Raimbault, S.; Manning, B.S.; Miroux, B.; Couplan, E.; Alves-Guerra, M.C.; Goubern, M.; Surwit, R.; Bouillaud, F.; Richard, D.; Collins, S.; Ricquier, D. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat. Genet., 2000, 26(4), 435-439.
[http://dx.doi.org/10.1038/82565] [PMID: 11101840]
[27]
Nicholls, D.G. Mitochondrial calcium function and dysfunction in the central nervous system. Biochim. Biophys. Acta, 2009, 1787(11), 1416-1424.
[http://dx.doi.org/10.1016/j.bbabio.2009.03.010] [PMID: 19298790]
[28]
Waldeck-Weiermair, M.; Malli, R.; Naghdi, S.; Trenker, M.; Kahn, M.J.; Graier, W.F. The contribution of UCP2 and UCP3 to mitochondrial Ca(2+) uptake is differentially determined by the source of supplied Ca(2+). Cell Calcium, 2010, 47(5), 433-440.
[http://dx.doi.org/10.1016/j.ceca.2010.03.004] [PMID: 20403634]
[29]
Takarada, T.; Fukumori, R.; Yoneda, Y. Mitochondrial uncoupling protein-2 in glutamate neurotoxicity. Nippon Yakurigaku Zasshi, 2013, 142(1), 13-16.
[http://dx.doi.org/10.1254/fpj.142.13] [PMID: 23842222]
[30]
Mehta, S.L.; Li, P.A. Neuroprotective role of mitochondrial uncoupling protein 2 in cerebral stroke. J. Cereb. Blood Flow Metab., 2009, 29(6), 1069-1078.
[http://dx.doi.org/10.1038/jcbfm.2009.4] [PMID: 19240738]
[31]
Orrenius, S.; Gogvadze, V.; Zhivotovsky, B. Calcium and mitochondria in the regulation of cell death. Biochem. Biophys. Res. Commun., 2015, 460(1), 72-81.
[http://dx.doi.org/10.1016/j.bbrc.2015.01.137] [PMID: 25998735]
[32]
He, M.; Zhang, T.; Fan, Y.; Ma, Y.; Zhang, J.; Jing, L.; Li, P.A. Deletion of mitochondrial uncoupling protein 2 exacerbates mitophagy and cell apoptosis after cerebral ischemia and reperfusion injury in mice. Int. J. Med. Sci., 2020, 17(17), 2869-2878.
[http://dx.doi.org/10.7150/ijms.49849] [PMID: 33162815]
[33]
Mattiasson, G.; Shamloo, M.; Gido, G.; Mathi, K.; Tomasevic, G.; Yi, S.; Warden, C.H.; Castilho, R.F.; Melcher, T.; Gonzalez-Zulueta, M.; Nikolich, K.; Wieloch, T. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat. Med., 2003, 9(8), 1062-1068.
[http://dx.doi.org/10.1038/nm903] [PMID: 12858170]
[34]
Teshima, Y.; Akao, M.; Jones, S.P.; Marbán, E. Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ. Res., 2003, 93(3), 192-200.
[http://dx.doi.org/10.1161/01.RES.0000085581.60197.4D] [PMID: 12855674]
[35]
Mizuno, T.; Miura-Suzuki, T.; Yamashita, H.; Mori, N. Distinct regulation of brain mitochondrial carrier protein-1 and uncoupling protein-2 genes in the rat brain during cold exposure and aging. Biochem. Biophys. Res. Commun., 2000, 278(3), 691-697.
[http://dx.doi.org/10.1006/bbrc.2000.3859] [PMID: 11095970]
[36]
Fleury, C.; Neverova, M.; Collins, S.; Raimbault, S.; Champigny, O.; Levi-Meyrueis, C.; Bouillaud, F.; Seldin, M.F.; Surwit, R.S.; Ricquier, D.; Warden, C.H. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat. Genet., 1997, 15(3), 269-272.
[http://dx.doi.org/10.1038/ng0397-269] [PMID: 9054939]
[37]
Rubattu, S.; Stanzione, R.; Bianchi, F.; Cotugno, M.; Forte, M.; Della Ragione, F.; Fioriniello, S.; D’Esposito, M.; Marchitti, S.; Madonna, M.; Baima, S.; Morelli, G.; Sciarretta, S.; Sironi, L.; Gelosa, P.; Volpe, M. Reduced brain UCP2 expression mediated by microRNA-503 contributes to increased stroke susceptibility in the high-salt fed stroke-prone spontaneously hypertensive rat. Cell Death Dis., 2017, 8(6) ,e2891.
[http://dx.doi.org/10.1038/cddis.2017.278] [PMID: 28640254]
[38]
Joseph, J.W.; Koshkin, V.; Zhang, C.Y.; Wang, J.; Lowell, B.B.; Chan, C.B.; Wheeler, M.B. Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes, 2002, 51(11), 3211-3219.
[http://dx.doi.org/10.2337/diabetes.51.11.3211] [PMID: 12401712]
[39]
Rubattu, S.; Bianchi, F.; Busceti, C.L.; Cotugno, M.; Stanzione, R.; Marchitti, S.; Di Castro, S.; Madonna, M.; Nicoletti, F.; Volpe, M. Differential modulation of AMPK/PPARα/UCP2 axis in relation to hypertension and aging in the brain, kidneys and heart of two closely related spontaneously hypertensive rat strains. Oncotarget, 2015, 6(22), 18800-18818.
[http://dx.doi.org/10.18632/oncotarget.4033] [PMID: 26023797]
[40]
Zhang, Y.; Mi, S.L.; Hu, N.; Doser, T.A.; Sun, A.; Ge, J.; Ren, J. Mitochondrial aldehyde dehydrogenase 2 accentuates aging-induced cardiac remodeling and contractile dysfunction: role of AMPK, Sirt1, and mitochondrial function. Free Radic. Biol. Med., 2014, 71, 208-220.
[http://dx.doi.org/10.1016/j.freeradbiomed.2014.03.018] [PMID: 24675227]
[41]
Ren, J.; Yang, L.; Zhu, L.; Xu, X.; Ceylan, A.F.; Guo, W.; Yang, J.; Zhang, Y. Akt2 ablation prolongs life span and improves myocardial contractile function with adaptive cardiac remodeling: role of Sirt1-mediated autophagy regulation. Aging Cell, 2017, 16(5), 976-987.
[http://dx.doi.org/10.1111/acel.12616] [PMID: 28681509]
[42]
Zhang, Y.; Babcock, S.A.; Hu, N.; Maris, J.R.; Wang, H.; Ren, J. Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function. BMC Med., 2012, 10, 40.
[http://dx.doi.org/10.1186/1741-7015-10-40] [PMID: 22524197]
[43]
Bano, D.; Nicotera, P. Ca2+ signals and neuronal death in brain ischemia. Stroke, 2007, 38(2)(Suppl.), 674-676.
[http://dx.doi.org/10.1161/01.STR.0000256294.46009.29] [PMID: 17261713]
[44]
Sanganalmath, S.K.; Gopal, P.; Parker, J.R.; Downs, R.K.; Parker, J.C., Jr; Dawn, B. Global cerebral ischemia due to circulatory arrest: insights into cellular pathophysiology and diagnostic modalities. Mol. Cell. Biochem., 2017, 426(1-2), 111-127.
[http://dx.doi.org/10.1007/s11010-016-2885-9] [PMID: 27896594]
[45]
Lai, T.W.; Zhang, S.; Wang, Y.T. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog. Neurobiol., 2014, 115, 157-188.
[http://dx.doi.org/10.1016/j.pneurobio.2013.11.006] [PMID: 24361499]
[46]
Rubattu, S.; Di Castro, S.; Cotugno, M.; Bianchi, F.; Mattioli, R.; Baima, S.; Stanzione, R.; Madonna, M.; Bozzao, C.; Marchitti, S.; Gelosa, P.; Sironi, L.; Pignieri, A.; Maldini, M.; Giusti, A.M.; Nardini, M.; Morelli, G.; Costantino, P.; Volpe, M. Protective effects of Brassica oleracea sprouts extract toward renal damage in high-salt-fed SHRSP: role of AMPK/PPARα/UCP2 axis. J. Hypertens., 2015, 33(7), 1465-1479.
[http://dx.doi.org/10.1097/HJH.0000000000000562] [PMID: 25807219]
[47]
Gallo, G.; Forte, M.; Stanzione, R.; Cotugno, M.; Bianchi, F.; Marchitti, S.; Berni, A.; Volpe, M.; Rubattu, S. Functional role of natriuretic peptides in risk assessment and prognosis of patients with mitral regurgitation. J. Clin. Med., 2020, 9(5) ,E1348.
[http://dx.doi.org/10.3390/jcm9051348] [PMID: 32380651]
[48]
Di Castro, S.; Scarpino, S.; Marchitti, S.; Bianchi, F.; Stanzione, R.; Cotugno, M.; Sironi, L.; Gelosa, P.; Duranti, E.; Ruco, L.; Volpe, M.; Rubattu, S. Differential modulation of uncoupling protein 2 in kidneys of stroke-prone spontaneously hypertensive rats under high-salt/low-potassium diet. Hypertension, 2013, 61(2), 534-541.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.00101] [PMID: 23297375]
[49]
Hou, X.; Shen, Y.H.; Li, C.; Wang, F.; Zhang, C.; Bu, P.; Zhang, Y. PPARalpha agonist fenofibrate protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress and MAPK activity. Biochem. Biophys. Res. Commun., 2010, 394(3), 653-659.
[http://dx.doi.org/10.1016/j.bbrc.2010.03.043] [PMID: 20226762]
[50]
Gelosa, P.; Banfi, C.; Gianella, A.; Brioschi, M.; Pignieri, A.; Nobili, E.; Castiglioni, L.; Cimino, M.; Tremoli, E.; Sironi, L. Peroxisome proliferator-activated receptor alpha agonism prevents renal damage and the oxidative stress and inflammatory processes affecting the brains of stroke-prone rats. J. Pharmacol. Exp. Ther., 2010, 335(2), 324-331.
[http://dx.doi.org/10.1124/jpet.110.171090] [PMID: 20671072]
[51]
Medvedev, A.V.; Snedden, S.K.; Raimbault, S.; Ricquier, D.; Collins, S. Transcriptional regulation of the mouse uncoupling protein-2 gene. Double E-box motif is required for peroxisome proliferator-activated receptor-gamma-dependent activation. J. Biol. Chem., 2001, 276(14), 10817-10823.
[http://dx.doi.org/10.1074/jbc.M010587200] [PMID: 11150307]
[52]
Nishijima, C.; Kimoto, K.; Arakawa, Y. Survival activity of troglitazone in rat motoneurones. J. Neurochem., 2001, 76(2), 383-390.
[http://dx.doi.org/10.1046/j.1471-4159.2001.00039.x] [PMID: 11208901]
[53]
Shimazu, T.; Inoue, I.; Araki, N.; Asano, Y.; Sawada, M.; Furuya, D.; Nagoya, H.; Greenberg, J.H. A peroxisome proliferator-activated receptor-gamma agonist reduces infarct size in transient but not in permanent ischemia. Stroke, 2005, 36(2), 353-359.
[http://dx.doi.org/10.1161/01.STR.0000152271.21943.a2] [PMID: 15618443]
[54]
Sundararajan, S.; Gamboa, J.L.; Victor, N.A.; Wanderi, E.W.; Lust, W.D.; Landreth, G.E. Peroxisome proliferator-activated receptor-gamma ligands reduce inflammation and infarction size in transient focal ischemia. Neuroscience, 2005, 130(3), 685-696.
[http://dx.doi.org/10.1016/j.neuroscience.2004.10.021] [PMID: 15590152]
[55]
Nakase, T.; Yoshida, Y.; Nagata, K. Amplified expression of uncoupling proteins in human brain ischemic lesions. Neuropathology, 2007, 27(5), 442-447.
[http://dx.doi.org/10.1111/j.1440-1789.2007.00815.x] [PMID: 18018477]
[56]
Dalgaard, L.T.; Andersen, G.; Larsen, L.H.; Sørensen, T.I.; Andersen, T.; Drivsholm, T.; Borch-Johnsen, K.; Fleckner, J.; Hansen, T.; Din, N.; Pedersen, O. Mutational analysis of the UCP2 core promoter and relationships of variants with obesity. Obes. Res., 2003, 11(11), 1420-1427.
[http://dx.doi.org/10.1038/oby.2003.191] [PMID: 14627764]
[57]
Lapice, E.; Pinelli, M.; Pisu, E.; Monticelli, A.; Gambino, R.; Pagano, G.; Valsecchi, S.; Cocozza, S.; Riccardi, G.; Vaccaro, O. Uncoupling protein 2 G(-866)A polymorphism: a new gene polymorphism associated with C-reactive protein in type 2 diabetic patients. Cardiovasc. Diabetol., 2010, 9, 68.
[http://dx.doi.org/10.1186/1475-2840-9-68] [PMID: 21029457]
[58]
Chai, Y.; Gu, B.; Qiu, J.R.; Yi, H.G.; Zhu, Q.; Zhang, L.; Hu, G. The uncoupling protein 2 -866G > a polymorphism is associated with the risk of ischemic stroke in Chinese type 2 diabetic patients. CNS Neurosci. Ther., 2012, 18(8), 636-640.
[http://dx.doi.org/10.1111/j.1755-5949.2012.00333.x] [PMID: 22613561]
[59]
Chai, Y.; Gu, B.; Qiu, J.R.; Yi, H.G.; Zhu, Q.; Zhang, L.; Hu, G. Effects of uncoupling protein 2 -866G/A polymorphism on platelet reactivity and prognosis in Chinese patients with type 2 diabetes and ischemic stroke. Int. J. Neurosci., 2013, 123(11), 752-758.
[http://dx.doi.org/10.3109/00207454.2013.798733] [PMID: 23621569]
[60]
Díaz-Maroto Cicuéndez, I.; Fernández-Díaz, E.; García-García, J.; Jordán, J.; Fernández-Cadenas, I.; Montaner, J.; Serrano-Heras, G.; Segura, T. The UCP2-866G/A polymorphism could be considered as a genetic marker of different functional prognosis in ischemic stroke after recanalization. Neuromolecular Med., 2017, 19(4), 571-578.
[http://dx.doi.org/10.1007/s12017-017-8470-x] [PMID: 29043564]
[61]
Wu, H.; Ye, M.; Liu, D.; Yang, J.; Ding, J.W.; Zhang, J.; Wang, X.A.; Dong, W.S.; Fan, Z.X.; Yang, J. UCP2 protect the heart from myocardial ischemia/reperfusion injury via induction of mitochondrial autophagy. J. Cell. Biochem., 2019, 120(9), 15455-15466.
[http://dx.doi.org/10.1002/jcb.28812] [PMID: 31081966]
[62]
Strøm, C.C.; Aplin, M.; Ploug, T.; Christoffersen, T.E.; Langfort, J.; Viese, M.; Galbo, H.; Haunsø, S.; Sheikh, S.P. Expression profiling reveals differences in metabolic gene expression between exercise-induced cardiac effects and maladaptive cardiac hypertrophy. FEBS J., 2005, 272(11), 2684-2695.
[http://dx.doi.org/10.1111/j.1742-4658.2005.04684.x] [PMID: 15943803]
[63]
Strøm, C.C.; Kruhøffer, M.; Knudsen, S.; Stensgaard-Hansen, F.; Jonassen, T.E.; Orntoft, T.F.; Haunsø, S.; Sheikh, S.P. Identification of a core set of genes that signifies pathways underlying cardiac hypertrophy. Comp. Funct. Genomics, 2004, 5(6-7), 459-470.
[http://dx.doi.org/10.1002/cfg.428] [PMID: 18629135]
[64]
Zhang, Y.; Li, L.; Hua, Y.; Nunn, J.M.; Dong, F.; Yanagisawa, M.; Ren, J. Cardiac-specific knockout of ET(A) receptor mitigates low ambient temperature-induced cardiac hypertrophy and contractile dysfunction. J. Mol. Cell Biol., 2012, 4(2), 97-107.
[http://dx.doi.org/10.1093/jmcb/mjs002] [PMID: 22442497]
[65]
Kong, X.; Liu, H.; He, X.; Sun, Y.; Ge, W. Unraveling the mystery of cold stress-induced myocardial injury. Front. Physiol., 2020, 11 ,580811.
[http://dx.doi.org/10.3389/fphys.2020.580811] [PMID: 33250775]
[66]
Gaussin, V.; Tomlinson, J.E.; Depre, C.; Engelhardt, S.; Antos, C.L.; Takagi, G.; Hein, L.; Topper, J.N.; Liggett, S.B.; Olson, E.N.; Lohse, M.J.; Vatner, S.F.; Vatner, D.E. Common genomic response in different mouse models of beta-adrenergic-induced cardiomyopathy. Circulation, 2003, 108(23), 2926-2933.
[http://dx.doi.org/10.1161/01.CIR.0000101922.18151.7B] [PMID: 14623810]
[67]
Murakami, K.; Mizushige, K.; Noma, T.; Tsuji, T.; Kimura, S.; Kohno, M. Perindopril effect on uncoupling protein and energy metabolism in failing rat hearts. Hypertension, 2002, 40(3), 251-255.
[http://dx.doi.org/10.1161/01.HYP.0000029094.85023.01] [PMID: 12215462]
[68]
Esfandiary, A.; Kutsche, H.S.; Schreckenberg, R.; Weber, M.; Pak, O.; Kojonazarov, B.; Sydykov, A.; Hirschhäuser, C.; Wolf, A.; Haag, D.; Hecker, M.; Fink, L.; Seeger, W.; Ghofrani, H.A.; Schermuly, R.T.; Weißmann, N.; Schulz, R.; Rohrbach, S.; Li, L.; Sommer, N.; Schlüter, K.D. Protection against pressure overload-induced right heart failure by uncoupling protein 2 silencing. Cardiovasc. Res., 2019, 115(7), 1217-1227.
[http://dx.doi.org/10.1093/cvr/cvz049] [PMID: 30850841]
[69]
Palmer, B.R.; Devereaux, C.L.; Dhamrait, S.S.; Mocatta, T.J.; Pilbrow, A.P.; Frampton, C.M.; Skelton, L.; Yandle, T.G.; Winterbourn, C.C.; Richards, A.M.; Montgomery, H.E.; Cameron, V.A. The common G-866A polymorphism of the UCP2 gene and survival in diabetic patients following myocardial infarction. Cardiovasc. Diabetol., 2009, 8, 31.
[http://dx.doi.org/10.1186/1475-2840-8-31] [PMID: 19527523]
[70]
Phulukdaree, A.; Moodley, D.; Khan, S.; Chuturgoon, A.A. Uncoupling protein 2 -866G/A and uncoupling protein 3 -55C/T polymorphisms in young South African Indian coronary artery disease patients. Gene, 2013, 524(2), 79-83.
[http://dx.doi.org/10.1016/j.gene.2013.04.048] [PMID: 23639961]
[71]
Matsunaga, T.; Gu, N.; Yamazaki, H.; Tsuda, M.; Adachi, T.; Yasuda, K.; Moritani, T.; Tsuda, K.; Nonaka, M.; Nishiyama, T. Association of UCP2 and UCP3 polymorphisms with heart rate variability in Japanese men. J. Hypertens., 2009, 27(2), 305-313.
[http://dx.doi.org/10.1097/HJH.0b013e32831ac967] [PMID: 19155787]
[72]
Kopelman, P.G. Obesity as a medical problem. Nature, 2000, 404(6778), 635-643.
[http://dx.doi.org/10.1038/35007508] [PMID: 10766250]
[73]
Sun, L.L.; Jiang, B.G.; Li, W.T.; Zou, J.J.; Shi, Y.Q.; Liu, Z.M. MicroRNA-15a positively regulates insulin synthesis by inhibiting uncoupling protein-2 expression. Diabetes Res. Clin. Pract., 2011, 91(1), 94-100.
[http://dx.doi.org/10.1016/j.diabres.2010.11.006] [PMID: 21146880]
[74]
Ren, J.; Pulakat, L.; Whaley-Connell, A.; Sowers, J.R. Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease. J. Mol. Med. (Berl.), 2010, 88(10), 993-1001.
[http://dx.doi.org/10.1007/s00109-010-0663-9] [PMID: 20725711]
[75]
Dalgaard, L.T. Genetic variance in uncoupling protein 2 in relation to obesity, type 2 diabetes, and related metabolic traits: Focus on the functional -866G>A promoter variant (rs659366). J. Obes., 2011, 2011 ,340241.
[http://dx.doi.org/10.1155/2011/340241] [PMID: 21603268]
[76]
Salopuro, T.; Pulkkinen, L.; Lindström, J.; Kolehmainen, M.; Tolppanen, A.M.; Eriksson, J.G.; Valle, T.T.; Aunola, S.; Ilanne-Parikka, P.; Keinänen-Kiukaanniemi, S.; Tuomilehto, J.; Laakso, M.; Uusitupa, M. Variation in the UCP2 and UCP3 genes associates with abdominal obesity and serum lipids: the Finnish Diabetes Prevention Study. BMC Med. Genet., 2009, 10, 94.
[http://dx.doi.org/10.1186/1471-2350-10-94] [PMID: 19769793]
[77]
Heidari, J.; Akrami, S.M.; Heshmat, R.; Amiri, P.; Fakhrzadeh, H.; Pajouhi, M. Association study of the -866G/A UCP2 gene promoter polymorphism with type 2 diabetes and obesity in a Tehran population: a case control study. Arch. Iran Med., 2010, 13(5), 384-390.
[PMID: 20804304]
[78]
Ochoa, M.C.; Santos, J.L.; Azcona, C.; Moreno-Aliaga, M.J.; Martínez-González, M.A.; Martínez, J.A.; Marti, A. Association between obesity and insulin resistance with UCP2-UCP3 gene variants in Spanish children and adolescents. Mol. Genet. Metab., 2007, 92(4), 351-358.
[http://dx.doi.org/10.1016/j.ymgme.2007.07.011] [PMID: 17870627]
[79]
Andersen, G.; Dalgaard, L.T.; Justesen, J.M.; Anthonsen, S.; Nielsen, T.; Thørner, L.W.; Witte, D.; Jørgensen, T.; Clausen, J.O.; Lauritzen, T.; Holmkvist, J.; Hansen, T.; Pedersen, O. The frequent UCP2 -866G>A polymorphism protects against insulin resistance and is associated with obesity: a study of obesity and related metabolic traits among 17 636 Danes. Int. J. Obes., 2013, 37(2), 175-181.
[http://dx.doi.org/10.1038/ijo.2012.22] [PMID: 22349573]
[80]
Krempler, F.; Esterbauer, H.; Weitgasser, R.; Ebenbichler, C.; Patsch, J.R.; Miller, K.; Xie, M.; Linnemayr, V.; Oberkofler, H.; Patsch, W. A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes, 2002, 51(11), 3331-3335.
[http://dx.doi.org/10.2337/diabetes.51.11.3331] [PMID: 12401727]
[81]
Xu, L.; Chen, S.; Zhan, L. Association of uncoupling protein-2 -866G/A and Ala55Val polymorphisms with susceptibility to type 2 diabetes mellitus: A meta-analysis of case-control studies. Medicine (Baltimore), 2021, 100(6) ,e24464.
[http://dx.doi.org/10.1097/MD.0000000000024464] [PMID: 33578539]
[82]
Yang, M.; Huang, Q.; Wu, J.; Yin, J.Y.; Sun, H.; Liu, H.L.; Zhou, H.H.; Liu, Z.Q. Effects of UCP2 -866 G/A and ADRB3 Trp64Arg on rosiglitazone response in Chinese patients with Type 2 diabetes. Br. J. Clin. Pharmacol., 2009, 68(1), 14-22.
[http://dx.doi.org/10.1111/j.1365-2125.2009.03431.x] [PMID: 19659999]
[83]
Xu, K.; Zhang, M.; Cui, D.; Fu, Y.; Qian, L.; Gu, R.; Wang, M.; Shen, C.; Yu, R.; Yang, T. UCP2 -866G/A and Ala55Val, and UCP3 -55C/T polymorphisms in association with type 2 diabetes susceptibility: a meta-analysis study. Diabetologia, 2011, 54(9), 2315-2324.
[http://dx.doi.org/10.1007/s00125-011-2245-y] [PMID: 21751002]
[84]
Willig, A.L.; Casazza, K.R.; Divers, J.; Bigham, A.W.; Gower, B.A.; Hunter, G.R.; Fernandez, J.R. Uncoupling protein 2 Ala55Val polymorphism is associated with a higher acute insulin response to glucose. Metabolism, 2009, 58(6), 877-881.
[http://dx.doi.org/10.1016/j.metabol.2009.02.016] [PMID: 19368944]
[85]
Vimaleswaran, K.S.; Radha, V.; Ghosh, S.; Majumder, P.P.; Sathyanarayana Rao, M.R.; Mohan, V. Uncoupling protein 2 and 3 gene polymorphisms and their association with type 2 diabetes in asian indians. Diabetes Technol. Ther., 2011, 13(1), 19-25.
[http://dx.doi.org/10.1089/dia.2010.0091] [PMID: 21175267]
[86]
Kaur, J. A comprehensive review on metabolic syndrome. Cardiol. Res. Pract., 2014, 2014 ,943162.
[http://dx.doi.org/10.1155/2014/943162] [PMID: 24711954]
[87]
Ford, E.S.; Li, C.; Sattar, N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care, 2008, 31(9), 1898-1904.
[http://dx.doi.org/10.2337/dc08-0423] [PMID: 18591398]
[88]
Ruiz-Ramírez, A.; Chávez-Salgado, M.; Peñeda-Flores, J.A.; Zapata, E.; Masso, F.; El-Hafidi, M. High-sucrose diet increases ROS generation, FFA accumulation, UCP2 level, and proton leak in liver mitochondria. Am. J. Physiol. Endocrinol. Metab., 2011, 301(6), E1198-E1207.
[http://dx.doi.org/10.1152/ajpendo.00631.2010] [PMID: 21917631]
[89]
Castrejón-Tellez, V.; Rodríguez-Pérez, J.M.; Pérez-Torres, I.; Pérez-Hernández, N.; Cruz-Lagunas, A.; Guarner-Lans, V.; Vargas-Alarcón, G.; Rubio-Ruiz, M.E. The effect of resveratrol and quercetin treatment on PPAR mediated uncoupling protein (UCP-) 1, 2, and 3 expression in visceral white adipose tissue from metabolic syndrome rats. Int. J. Mol. Sci., 2016, 17(7) ,E1069.
[http://dx.doi.org/10.3390/ijms17071069] [PMID: 27399675]
[90]
Lu, L.; Sun, X.; Chen, C.; Qin, Y.; Guo, X. Shexiang baoxin pill, derived from the traditional chinese medicine, provides protective roles against cardiovascular diseases. Front. Pharmacol., 2018, 9, 1161.
[http://dx.doi.org/10.3389/fphar.2018.01161] [PMID: 30487746]
[91]
Wei, D.; Zheng, N.; Zheng, L.; Wang, L.; Song, L.; Sun, L. Shexiang baoxin pill corrects metabolic disorders in a rat model of metabolic syndrome by targeting mitochondria. Front. Pharmacol., 2018, 9, 137.
[http://dx.doi.org/10.3389/fphar.2018.00137] [PMID: 29551973]
[92]
Abbasalizad Farhangi, M.; Mohseni, F.; Farajnia, S.; Jafarabadi, M.A. Major components of metabolic syndrome and nutritional intakes in different genotype of UCP2 -866G/A gene polymorphisms in patients with NAFLD. J. Transl. Med., 2016, 14(1), 177.
[http://dx.doi.org/10.1186/s12967-016-0936-3] [PMID: 27301474]
[93]
Lim, K.I.; Shin, Y.A. Impact of UCP2 polymorphism on long-term exercise-mediated changes in adipocytokines and markers of metabolic syndrome. Aging Clin. Exp. Res., 2014, 26(5), 491-496.
[http://dx.doi.org/10.1007/s40520-014-0213-3] [PMID: 24659521]
[94]
Donadelli, M.; Dando, I.; Fiorini, C.; Palmieri, M. UCP2, a mitochondrial protein regulated at multiple levels. Cell. Mol. Life Sci., 2014, 71(7), 1171-1190.
[http://dx.doi.org/10.1007/s00018-013-1407-0] [PMID: 23807210]
[95]
Crepaldi, G.; Carruba, M.; Comaschi, M.; Del Prato, S.; Frajese, G.; Paolisso, G. Dipeptidyl peptidase 4 (DPP-4) inhibitors and their role in Type 2 diabetes management. J. Endocrinol. Invest., 2007, 30(7), 610-614.
[http://dx.doi.org/10.1007/BF03346357] [PMID: 17848846]
[96]
Lemos, N.E.; Dieter, C.; Carlessi, R.; Rheinheimer, J.; Brondani, L.A.; Leitão, C.B.; Bauer, A.C.; Crispim, D. Renal effects of exendin-4 in an animal model of brain death. Mol. Biol. Rep., 2019, 46(2), 2197-2207.
[http://dx.doi.org/10.1007/s11033-019-04674-1] [PMID: 30759298]
[97]
Liu, L.; Liu, J.; Tian, X.Y.; Wong, W.T.; Lau, C.W.; Xu, A.; Xu, G.; Ng, C.F.; Yao, X.; Gao, Y.; Huang, Y. Uncoupling protein-2 mediates DPP-4 inhibitor-induced restoration of endothelial function in hypertension through reducing oxidative stress. Antioxid. Redox Signal., 2014, 21(11), 1571-1581.
[http://dx.doi.org/10.1089/ars.2013.5519] [PMID: 24328731]
[98]
Anedda, A.; Rial, E.; González-Barroso, M.M. Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels. J. Endocrinol., 2008, 199(1), 33-40.
[http://dx.doi.org/10.1677/JOE-08-0278] [PMID: 18687824]
[99]
Wang, Q.; Zhang, M.; Liang, B.; Shirwany, N.; Zhu, Y.; Zou, M.H. Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2. PLoS One, 2011, 6(9) ,e25436.
[http://dx.doi.org/10.1371/journal.pone.0025436] [PMID: 21980456]
[100]
Berger, J.; Moller, D.E. The mechanisms of action of PPARs. Annu. Rev. Med., 2002, 53, 409-435.
[http://dx.doi.org/10.1146/annurev.med.53.082901.104018] [PMID: 11818483]
[101]
Olefsky, J.M.; Saltiel, A.R. PPAR gamma and the treatment of insulin resistance. Trends Endocrinol. Metab., 2000, 11(9), 362-368.
[http://dx.doi.org/10.1016/S1043-2760(00)00306-4] [PMID: 11042466]
[102]
Gurnell, M. Peroxisome proliferator-activated receptor gamma and the regulation of adipocyte function: lessons from human genetic studies. Best Pract. Res. Clin. Endocrinol. Metab., 2005, 19(4), 501-523.
[http://dx.doi.org/10.1016/j.beem.2005.10.001] [PMID: 16311214]
[103]
Staels, B.; Fruchart, J.C. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes, 2005, 54(8), 2460-2470.
[http://dx.doi.org/10.2337/diabetes.54.8.2460] [PMID: 16046315]
[104]
Camirand, A.; Marie, V.; Rabelo, R.; Silva, J.E. Thiazolidinediones stimulate uncoupling protein-2 expression in cell lines representing white and brown adipose tissues and skeletal muscle. Endocrinology, 1998, 139(1), 428-431.
[http://dx.doi.org/10.1210/endo.139.1.5808] [PMID: 9421444]
[105]
Strobel, A.; Siquier, K.; Zilberfarb, V.; Strosberg, A.D.; Issad, T. Effect of thiazolidinediones on expression of UCP2 and adipocyte markers in human PAZ6 adipocytes. Diabetologia, 1999, 42(5), 527-533.
[http://dx.doi.org/10.1007/s001250051190] [PMID: 10333043]
[106]
Viguerie-Bascands, N.; Saulnier-Blache, J.S.; Dandine, M.; Dauzats, M.; Daviaud, D.; Langin, D. Increase in uncoupling protein-2 mRNA expression by BRL49653 and bromopalmitate in human adipocytes. Biochem. Biophys. Res. Commun., 1999, 256(1), 138-141.
[http://dx.doi.org/10.1006/bbrc.1999.0303] [PMID: 10066437]
[107]
Chan, S.H.; Wu, C.A.; Wu, K.L.; Ho, Y.H.; Chang, A.Y.; Chan, J.Y. Transcriptional upregulation of mitochondrial uncoupling protein 2 protects against oxidative stress-associated neurogenic hypertension. Circ. Res., 2009, 105(9), 886-896.
[http://dx.doi.org/10.1161/CIRCRESAHA.109.199018] [PMID: 19762685]
[108]
Brabazon, F.; Bermudez, S.; Shaughness, M.; Khayrullina, G.; Byrnes, K.R. The effects of insulin on the inflammatory activity of BV2 microglia. PLoS One, 2018, 13(8) ,e0201878.
[http://dx.doi.org/10.1371/journal.pone.0201878] [PMID: 30148836]
[109]
Ozturk, F.; Gul, M.; Esrefoglu, M.; Ates, B. The contradictory effects of nitric oxide in caerulein-induced acute pancreatitis in rats. Free Radic. Res., 2008, 42(4), 289-296.
[http://dx.doi.org/10.1080/10715760801930730] [PMID: 18404527]
[110]
Walthers, E.A.; Bradford, C.S.; Moore, F.L. Cloning, pharmacological characterization and tissue distribution of an ORL1 opioid receptor from an amphibian, the rough-skinned newt Taricha granulosa. J. Mol. Endocrinol., 2005, 34(1), 247-256.
[http://dx.doi.org/10.1677/jme.1.01687] [PMID: 15691892]
[111]
Selimovic, D.; Hassan, M.; Haikel, Y.; Hengge, U.R. Taxol-induced mitochondrial stress in melanoma cells is mediated by activation of c-Jun N-terminal kinase (JNK) and p38 pathways via uncoupling protein 2. Cell. Signal., 2008, 20(2), 311-322.
[http://dx.doi.org/10.1016/j.cellsig.2007.10.015] [PMID: 18068334]
[112]
Liu, D.; Ma, Z.; Di, S.; Yang, Y.; Yang, J.; Xu, L.; Reiter, R.J.; Qiao, S.; Yuan, J. AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis. Free Radic. Biol. Med., 2018, 129, 59-72.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.08.032] [PMID: 30172748]
[113]
Pagliaro, B.; Santolamazza, C.; Simonelli, F.; Rubattu, S. Phytochemical compounds and protection from cardiovascular diseases: A state of the art. BioMed Res. Int., 2015, 2015 ,918069.
[http://dx.doi.org/10.1155/2015/918069] [PMID: 26504846]
[114]
Clarke, J.D.; Riedl, K.; Bella, D.; Schwartz, S.J.; Stevens, J.F.; Ho, E. Comparison of isothiocyanate metabolite levels and histone deacetylase activity in human subjects consuming broccoli sprouts or broccoli supplement. J. Agric. Food Chem., 2011, 59(20), 10955-10963.
[http://dx.doi.org/10.1021/jf202887c] [PMID: 21928849]
[115]
Kim, S.Y.; Yoon, S.; Kwon, S.M.; Park, K.S.; Lee-Kim, Y.C. Kale juice improves coronary artery disease risk factors in hypercholesterolemic men. Biomed. Environ. Sci., 2008, 21(2), 91-97.
[http://dx.doi.org/10.1016/S0895-3988(08)60012-4] [PMID: 18548846]
[116]
Bhagani, H.; Nasser, S.A.; Dakroub, A.; El-Yazbi, A.F.; Eid, A.A.; Kobeissy, F.; Pintus, G.; Eid, A.H. The mitochondria: A target of polyphenols in the treatment of diabetic cardiomyopathy. Int. J. Mol. Sci., 2020, 21(14) ,E4962.
[http://dx.doi.org/10.3390/ijms21144962] [PMID: 32674299]
[117]
Diao, J.; Wei, J.; Yan, R.; Fan, G.; Lin, L.; Chen, M. Effects of resveratrol on regulation on UCP2 and cardiac function in diabetic rats. J. Physiol. Biochem., 2019, 75(1), 39-51.
[http://dx.doi.org/10.1007/s13105-018-0648-7] [PMID: 30225723]

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