Genetic deletion in uncoupling protein 3 augments 18F-fluorodeoxyglucose cardiac uptake in the ischemic heart

BMC Cardiovascular Disorders

Alberto Cuocolo³  Arturo Brunetti⁴  Mario Petretta¹  Giovanni Esposito³  Gabriele G Schiattarella³  Matteo Gramanzini²  Michele Larobina²  Mariarosaria Panico²  Adelaide Greco⁴  Maria Piera Petretta³  Sara Gargiulo² 

[1] Department of Translational Medical Sciences, University Federico II, Naples, Italy;Institute of Biostructure and Bioimaging, National Council of Research, Naples, Italy;Department of Advanced Biomedical Sciences, University Federico II, Via Pansini 5, 80131 Naples, Italy;CEINGE Scarl, Naples, Italy

关键词: Positron emission tomography;    Glucose metabolism;    Myocardial infarction;    Uncoupling protein;   

Others  :  1088474
DOI  :  10.1186/1471-2261-14-98

 received in 2014-04-30, accepted in 2014-07-30,  发布年份 2014

【 摘 要 】

Background

We investigated the effects of uncoupling protein 3 (UCP3) genetic deletion on ¹⁸F-fluorodeoxyglucose (FDG) cardiac uptake by positron emission tomography (PET)/computed tomography (CT) dedicated animal system after permanent coronary artery ligation.

Methods

Cardiac ¹⁸F-FDG PET/CT was performed in UCP3 knockout (UCP3^-/-) and wild-type (WT) mice one week after induction of myocardial infarction or sham procedure.

Results

In sham-operated mice no difference in left ventricular (LV) volume was detectable between WT and UCP3^-/-. After myocardial infarction, LV volume was higher in both WT and UCP3^-/- compared to sham animals, with a significant interaction (p < 0.05) between genotype and myocardial infarction. In sham-operated animals no difference in FDG standardized uptake value (SUV) was detectable between WT (1.8 ± 0.6) and UCP3^-/- (1.8 ± 0.6). After myocardial infarction SUV was significantly higher in remote areas than in infarcted territories in both UCP3-/- and WT mice (both p < 0.01). Moreover, in remote areas, SUV was significantly higher (p < 0.001) in UCP3-/- as compared to WT, while in the infarcted territory SUV was comparable (p = 0.29). A significant relationship (r = 0.68, p < 0.001) between LV volume and SUV was found.

Conclusions

In a mice model of permanent coronary occlusion, UCP3 deficiency results in a metabolic shift that favored glycolytic metabolism and increased FDG uptake in remote areas.

【 授权许可】

   
2014 Gargiulo et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Mailloux RJ, Harper ME: Uncoupling proteins and the control of mitochondrial reactive oxygen species production. Free Radic Biol Med 2011, 51:1106-1115.
• [2]Seifert EL, Bézaire V, Estey C, Harper ME: Essential role for uncoupling protein-3 in mitochondrial adaptation to fasting but not in fatty acid oxidation or fatty acid anion export. J Biol Chem 2008, 283:25124-25131.
• [3]MacLellan JD, Gerrits MF, Gowing A, Smith PJ, Wheeler MB, Harper ME: Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells. Diabetes 2005, 54:2343-2350.
• [4]Bezaire V, Seifert EL, Harper ME: Uncoupling protein-3: clues in an ongoing mitochondrial mystery. FASEB J 2007, 21:312-324.
• [5]Sack MN: Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance. Cardiovasc Res 2006, 72:210-219.
• [6]Bodyak N, Rigor DL, Chen YS, Han Y, Bisping E, Pu WT, Kang PM: Uncoupling protein 2 modulates cell viability in adult rat cardiomyocytes. Am J Physiol Heart Circ Physiol 2007, 293:H829-H835.
• [7]Ljubicic V, Adhihetty PJ, Hood DA: Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis. J Appl Physiol 2004, 97:976-983.
• [8]Nabben M, Hoeks J: Mitochondrial uncoupling protein 3 and its role in cardiac- and skeletal muscle metabolism. Physiol Behav 2008, 94:259-269.
• [9]Essop MF, Razeghi P, McLeod C, Young ME, Taegtmeyer H, Sack MN: Hypoxia-induced decrease of UCP3 gene expression in rat heart parallels metabolic gene switching but fails to affect mitochondrial respiratory coupling. Biochem Biophys Res Commun 2004, 314:561-564.
• [10]Perrino C, Schiattarella GG, Sannino A, Pironti G, Petretta MP, Cannavo A, Gargiulo G, Ilardi F, Magliulo F, Franzone A, Carotenuto G, Serino F, Altobelli GG, Cimini V, Cuocolo A, Lombardi A, Goglia F, Indolfi C, Trimarco B, Esposito G: Genetic deletion of uncoupling protein 3 exaggerates apoptotic cell death in the ischemic heart leading to heart failure. J Am Heart Assoc 2013, 2:e000086.
• [11]Vidal-Puig AJ, Grujic D, Zhang CY, Hagen T, Boss O, Ido Y, Szczepanik A, Wade J, Mootha V, Cortright R, Muoio DM, Lowell BB: Energy metabolism in uncoupling protein 3 gene knockout mice. J Biol Chem 2000, 275:16258-16266.
• [12]Curcio A, Noma T, Naga Prasad SV, Wolf MJ, Lemaire A, Perrino C, Mao L, Rockman HA: Competitive displacement of phosphoinositide 3-kinase from beta-adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling. Am J Physiol Heart Circ Physiol 2006, 291:H1754-H1760.
• [13]Esposito G, Perrino C, Cannavo A, Schiattarella GG, Borgia F, Sannino A, Pironti G, Gargiulo G, Di Serafino L, Franzone A, Scudiero L, Grieco P, Indolfi C, Chiariello M: EGFR trans-activation by urotensin II receptor is mediated by beta-arrestin recruitment and confers cardioprotection in pressure overload induced cardiac hypertrophy. Basic Res Cardiol 2011, 106:577-589.
• [14]Greco A, Petretta MP, Larobina M, Gargiulo S, Panico M, Nekolla SG, Esposito G, Petretta M, Brunetti A, Cuocolo A: Reproducibility and accuracy of noninvasive measurement of infarct size in mice with high-resolution PET/CT. J Nucl Cardiol 2012, 19:492-499.
• [15]Higuchi T, Nekolla SG, Jankaukas A, Weber AW, Huisman MC, Reder S, Ziegler SI, Schwaiger M, Bengel FM: Characterization of normal and infarcted rat myocardium using a combination of small-animal PET and clinical MRI. J Nucl Med 2007, 48:288-294.
• [16]Nekolla SG, Miethaner C, Nguyen N, Ziegler SI, Schwaiger M: Reproducibility of polar map generation and assessment of defect severity and extent assessment in myocardial perfusion imaging using positron emission tomography. Eur J Nucl Med 1998, 25:1313-1321.
• [17]Himms-Hagen J, Harper ME: Physiological role of UCP3 may be export of fatty acids from mitochondria when fatty acid oxidation predominates: an hypothesis. Exp Biol Med 2001, 226:78-84.
• [18]Argyropoulos G, Brown AM, Willi SM, Zhu J, He Y, Reitman M, Gevao SM, Spruill I, Garvey WT: Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes. J Clin Invest 1998, 102:1345-1351.
• [19]Bezaire V, Hofmann W, Kramer JK, Kozak LP, Harper ME: Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3-/- and wild-type mice. Am J Physiol Endocrinol Metab 2001, 281:E975-E982.
• [20]Lu Z, Sack MN: ATF-1 is a hypoxia-responsive transcriptional activator of skeletal muscle mitochondrial-uncoupling protein 3. J Biol Chem 2008, 283:23410-23418.
• [21]Cadenas S, Aragonés J, Landàzuri MO: Mitochondrial reprogramming through cardiac oxygen sensor in ischemic heart disease. Cardiovasc Res 2010, 88:219-228.
• [22]Safari F, Anvari Z, Moshtaghioun S, Javan M, Bayat G, Forosh SS, Hekmatimoghaddam S: Differential expression of cardiac uncoupling proteins 2 and 3 in response to myocardial ischemia-reperfusion in rats. Life Sci 2014, 98:68-74.
• [23]Laskowski KR, Russell RR 3rd: Uncoupling proteins in heart failure. Curr Heart Fail Rep 2008, 5:75-79.
• [24]Anedda A, López-Bernardo E, Acosta-Iborra B, Saadeh Suleiman M, Landázuri MO, Cadenas S: The transcription factor Nrf2 promotes survival by enhancing the expression of uncoupling protein 3 under conditions of oxidative stress. Free Radic Biol Med 2013, 61C:395-407.
• [25]Ozcan C, Palmeri M, Horvath TL, Russell KS, Russell RR 3rd: Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning. Am J Physiol Heart Circ Physiol 2013, 304:H1192-H1200.
• [26]Lopaschuk G: The role of fatty acid oxidation in cardiac ischemia and reperfusion. Adv Stud Med 2004, 4:S803-S807.
• [27]Senese R, Valli V, Moreno M, Lombardi A, Busiello RA, Cioffi F, Silvestri E, Goglia F, Lanni A, de Lange P: Uncoupling protein 3 expression levels influence insulin sensitivity, fatty acid oxidation, and related signaling pathways. Pflugers Arch 2011, 461:153-164.
• [28]Mailloux RJ, Dumouchel T, Aguer C, de Kemp R, Beanlands R, Harper ME: Hexokinase II acts through UCP3 to suppress mitochondrial reactive oxygen species production and maintain aerobic respiration. Biochem J 2011, 437:301-311.