{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:17:07Z","timestamp":1785403027451,"version":"3.56.0"},"reference-count":34,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["268555672-SFB 1213, Project B05"],"award-info":[{"award-number":["268555672-SFB 1213, Project B05"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"award":["268555672-SFB 1213, Project B05"],"award-info":[{"award-number":["268555672-SFB 1213, Project B05"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Uncoupling protein 2 (UCP2) is expressed in various tissues throughout the body, but its expression in the spleen exceeds that of other organs. However, the precise function of UCP2 for spleen physiology is unclear. The spleen acts as a hub connecting the nervous system and immune system to cardiovascular and metabolic diseases. Here, we analyzed the impact of hypertension on the spleen and the role of UCP2 in this process. Experiments were performed with UCP2-knockout rats and their wild-type littermates. Hypertension was induced by administering the nitric oxide inhibitor L-NAME via tap water. Genetic depletion of UCP2 increased spleen size (splenomegaly) and strongly impaired the expression of genes coding for mitochondrial proteins. Among them, genes coding for proteins involved in oxidative metabolism, such as pyruvate dehydrogenase alpha 1, and the detoxification of reactive oxygen species were down-regulated. Collectively, these alterations in metabolism favor glycolysis and proliferation. Moreover, NOS3 was among the strongest down-regulated genes in UCP2\u2212\/\u2212 rats, and the inhibition of nitric oxide synthase by L-NAME mimicked large parts of the expression profile. Neither the depletion of UCP2 nor L-NAME-induced hypertension or combinations thereof affected chronic inflammation. In summary, UCP2 controls fuel consumption in splenic cells in a nitric-oxide-dependent way.<\/jats:p>","DOI":"10.3390\/cimb48080775","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:09:42Z","timestamp":1785398982000},"page":"775","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Uncoupling Protein 2 and Nitric Oxide Deficiency Favor Glycolytic Pathways and Organ Growth in the Rat Spleen"],"prefix":"10.3390","volume":"48","author":[{"given":"Lea","family":"Wagner","sequence":"first","affiliation":[{"name":"Physiologisches Institut, Justus-Liebig-Universit\u00e4t, 35392 Gie\u00dfen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Schreckenberg","sequence":"additional","affiliation":[{"name":"Physiologisches Institut, Justus-Liebig-Universit\u00e4t, 35392 Gie\u00dfen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6457-0944","authenticated-orcid":false,"given":"Nadja","family":"Itani","sequence":"additional","affiliation":[{"name":"Physiologisches Institut, Justus-Liebig-Universit\u00e4t, 35392 Gie\u00dfen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1253-8783","authenticated-orcid":false,"given":"Tsuneshiro","family":"Sato","sequence":"additional","affiliation":[{"name":"Physiologisches Institut, Justus-Liebig-Universit\u00e4t, 35392 Gie\u00dfen, Germany"},{"name":"Department of Anesthesiology and Intensive Care, Hamamatsu University of Medicine, Hamamatsu 431-3192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Sperhake","sequence":"additional","affiliation":[{"name":"Physiologisches Institut, Justus-Liebig-Universit\u00e4t, 35392 Gie\u00dfen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yva","family":"Cesar","sequence":"additional","affiliation":[{"name":"Physiologisches Institut, Justus-Liebig-Universit\u00e4t, 35392 Gie\u00dfen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6093-4919","authenticated-orcid":false,"given":"Klaus-Dieter","family":"Schl\u00fcter","sequence":"additional","affiliation":[{"name":"Physiologisches Institut, Justus-Liebig-Universit\u00e4t, 35392 Gie\u00dfen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lori, A., Perrotta, M., Lembo, G., and Carnevale, D. (2017). The spleen: A hub connecting the nervous and immune systems in cardiovascular and metabolic diseases. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18061216"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"42307","DOI":"10.1074\/jbc.M306951200","article-title":"Bone marrow transplantation reveals the in vivo expression of the mitochondrial uncoupling protein 2 in immune and nonimmune cells during inflammation","volume":"278","author":"Rousset","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cellimm.2013.10.002","article-title":"Mitochondrial uncoupling protein 2 protects splenocytes from oxidative stress-induced apoptosis during pathogen activation","volume":"286","author":"Cao","year":"2013","journal-title":"Cell. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"26268","DOI":"10.1074\/jbc.M202535200","article-title":"No evidence for a basal, retinoic, or superoxide-induced uncoupling activity of the uncoupling protein 2 present in spleen or lung mitochondria","volume":"277","author":"Couplan","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/sj.ijo.0802257","article-title":"Uncoupling protein-2 and 3 influence obesity and inflammation in transgenic mice","volume":"27","author":"Horvath","year":"2003","journal-title":"Int. J. Obes."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8705","DOI":"10.1074\/jbc.M006938200","article-title":"Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation","volume":"276","author":"Pecqueur","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kutsche, H.S., Schreckenberg, R., Weber, M., Hirschh\u00e4user, C., Rohrbach, S., Li, L., Niemann, B., Schulz, R., and Schl\u00fcter, K.-D. (2020). Alterations in glucose metabolism during the transition to heart failure: The contribution of UCP-2. Cells, 9.","DOI":"10.3390\/cells9030552"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1089\/ars.2021.0258","article-title":"Uncoupling proteins in striated muscles","volume":"37","author":"Kutsche","year":"2022","journal-title":"Antioxid. Redox Signal."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s00424-021-02629-9","article-title":"Effects of voluntary exercise on the expression of browning markers in visceral and subcutaneous fat tissue of normotensive and spontaneously hypertensive rats","volume":"474","author":"Karadedeli","year":"2022","journal-title":"Pflugers. Arch."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3211","DOI":"10.2337\/diabetes.51.11.3211","article-title":"Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet","volume":"51","author":"Joseph","year":"2002","journal-title":"Diabetes"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"500","DOI":"10.5483\/BMBRep.2022.55.10.056","article-title":"UCP2 KO mice exhibit ameliorated obesity and inflammation induced by high-fat diet feeding","volume":"55","author":"Kim","year":"2022","journal-title":"BMP Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Schreckenberg, R., Wolf, A., Troidl, C., Simsekyilmaz, S., and Schl\u00fcter, K.-D. (2021). Pro-inflammatory vascular stress in spontaneously hypertensive rats associated with high physical activity cannot be attenuated by aldosterone blockade. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.699283"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1470320317706653","DOI":"10.1177\/1470320317706653","article-title":"Recruitment of macrophages from the spleen contributes to myocardial fibrosis and hypertension induced by angiotensin II","volume":"18","author":"Wang","year":"2017","journal-title":"J. Renin-Angiotensin-Aldosterone Syst."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1089\/ars.2014.6139","article-title":"Specific mechanisms underlying right heart failure: The missing upregulation of superoxide dismutase-2 and its decisive role in antioxidative defense","volume":"23","author":"Schreckenberg","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1159\/000339423","article-title":"Spleen size in idiopathic and heritable pulmonary arterial hypertension","volume":"85","author":"Tonelli","year":"2013","journal-title":"Respiration"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"103308","DOI":"10.1016\/j.redox.2024.103308","article-title":"Inhibition of MMP2 activity mitigates N-omega-nitro-l-arginine-methyl ester (L-NAME)-induced right heart failure","volume":"76","author":"Schreckenberg","year":"2024","journal-title":"Redox Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Schreckenberg, R., Horn, A.-M., da Costa Rebelo, R.M., Simsekyilmaz, S., Niemann, B., Li, L., Rohrbach, S., and Schl\u00fcter, K.-D. (2017). Effects of 6-months\u2018 exercise on cardicac function, structure and metabolism in female hypertensive rats\u2013the decisive role of lysyl oxidase and collagen III. Front. Physiol., 8.","DOI":"10.3389\/fphys.2017.00556"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"He, H., Wang, L., Qiao, Y., Zhou, Q., Li, H., Chen, S., Yin, D., Huang, Q., and He, M. (2020). Doxorubicin induces endotheliotoxicity and mitochondrial dysfunction via ROS\/eNOS\/NO pathway. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01531"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7391","DOI":"10.18632\/oncotarget.14080","article-title":"Swimming attenuates inflammation, oxidative stress, and apoptosis in a rat model od dextran sulfate sodium-induced chronic colitis","volume":"8","author":"Qin","year":"2017","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1016\/j.lfs.2007.03.009","article-title":"Splenic hemodynamics and decreased endothelial nitric oxide synthase in the spleen of rats with liver cirrhosis","volume":"80","author":"Yamaguchi","year":"2007","journal-title":"Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17983","DOI":"10.1038\/s41598-018-36297-0","article-title":"Integrated analysis of microRNA and mRNA expression profiles in splenomegaly induced by non-cirrhotic portal hypertension in rats","volume":"8","author":"Saruwatari","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1016\/j.bbabio.2011.06.002","article-title":"Absence of mitochondrial uncoupling protein 3: Effect of thymus and spleen in the fed and fasted mice","volume":"1807","author":"Kelly","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"112529","DOI":"10.1016\/j.ecoenv.2021.112529","article-title":"Antagonizing effects of curcumin against mercury-induced autophagic death and trace elements disorder by regulating PI3K\/AKT and Nrf2 pathway in the spleen","volume":"222","author":"Zhao","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1369\/0022155417722118","article-title":"Euptox A induces G I arrest and autophagy via p38 MAPK- and PI3K\/AKT\/mTOR-mediated pathways in mouse splenocytes","volume":"65","author":"Mo","year":"2017","journal-title":"J. Histochem. Cytochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E1197","DOI":"10.1152\/ajpendo.2001.281.6.E1197","article-title":"Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPAR\u03b1 via a PPAR\u03b1.mediated pathway","volume":"281","author":"Armstrong","year":"2001","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1159\/000345043","article-title":"L-Deprenyl reverses age-associated decline in splenic norepinephrine, IL-2 and IFN-\u03b3 production in old female F344 rats","volume":"20","author":"ThyagaRajan","year":"2013","journal-title":"Neuroimmunomodulation"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Schulz, R., and Schl\u00fcter, K.-D. (2023). Importance of mitochondria in cardiac pathologies: Focus on uncoupling proteins and monoamine oxidase. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076459"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e009372","DOI":"10.1161\/JAHA.118.009372","article-title":"CD4+ regulatory T lymphocytes prevent impaired cerebral blood flow in angiotensin II-induced hypertension","volume":"8","author":"Iulita","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1189\/jlb.3HI0914-453R","article-title":"Differential effects of IFN-\u03b2 on IL-12, IL-23, and IL-10 expression in TLR-stimulated dendritic cells","volume":"98","author":"Yen","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.cyto.2006.07.012","article-title":"The uncoupling protein 2 modulates the cytokine balance in innate immunity","volume":"35","author":"Rousset","year":"2006","journal-title":"Cytokine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1093\/ndt\/gfs440","article-title":"Obesity-related chronic kidney disease is associated with spleen-derived IL-10","volume":"28","author":"Gotoh","year":"2013","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9563","DOI":"10.1038\/s41598-021-89104-8","article-title":"Cholinergic stimulation with pyridostigmine modulates a heart-spleen axis after acute myocardial infarction in spontaneously hypertensive rats","volume":"11","author":"Bandoni","year":"2011","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1161\/CIRCRESAHA.112.277475","article-title":"Neurohormonal modulation of the innate immune system is proinflammatory in the prehypertensive spontaneously rat, a genetic model of essential hypertension","volume":"111","author":"Harwani","year":"2012","journal-title":"Circ. Res."},{"key":"ref_34","first-page":"2217","article-title":"Crosstalk between the heart and peripheral organs in heart failure","volume":"48","author":"Jahng","year":"2006","journal-title":"Exp. Mol. Med."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/8\/775\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:56:42Z","timestamp":1785401802000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/8\/775"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":34,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cimb48080775"],"URL":"https:\/\/doi.org\/10.3390\/cimb48080775","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]}}}