{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T01:03:04Z","timestamp":1778893384113,"version":"3.51.4"},"reference-count":43,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,6,19]],"date-time":"2019-06-19T00:00:00Z","timestamp":1560902400000},"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":["SFB834 A5"],"award-info":[{"award-number":["SFB834 A5"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislaufforschung","doi-asserted-by":"publisher","award":["81X2200109"],"award-info":[{"award-number":["81X2200109"]}],"id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The AMP-activated protein kinase (AMPK) is an energy sensing kinase that is activated by a drop in cellular ATP levels. Although several studies have addressed the role of the AMPK\u03b11 subunit in monocytes and macrophages, little is known about the \u03b12 subunit. The aim of this study was to assess the consequences of AMPK\u03b12 deletion on protein expression in monocytes\/macrophages, as well as on atherogenesis. A proteomics approach was applied to bone marrow derived monocytes from wild-type mice versus mice specifically lacking AMPK\u03b12 in myeloid cells (AMPK\u03b12\u2206MC mice). This revealed differentially expressed proteins, including methyltransferases. Indeed, AMPK\u03b12 deletion in macrophages increased the ratio of S-adenosyl methionine to S-adenosyl homocysteine and increased global DNA cytosine methylation. Also, methylation of the vascular endothelial growth factor and matrix metalloproteinase-9 (MMP9) genes was increased in macrophages from AMPK\u03b12\u2206MC mice, and correlated with their decreased expression. To link these findings with an in vivo phenotype, AMPK\u03b12\u2206MC mice were crossed onto the ApoE-\/- background and fed a western diet. ApoExAMPK\u03b12\u2206MC mice developed smaller atherosclerotic plaques than their ApoEx\u03b12fl\/fl littermates, that contained fewer macrophages and less MMP9 than plaques from ApoEx\u03b12fl\/fl littermates. These results indicate that the AMPK\u03b12 subunit in myeloid cells influences DNA methylation and thus protein expression and contributes to the development of atherosclerotic plaques.<\/jats:p>","DOI":"10.3390\/ijms20123005","type":"journal-article","created":{"date-parts":[[2019,6,20]],"date-time":"2019-06-20T10:49:59Z","timestamp":1561027799000},"page":"3005","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Myeloid-Specific Deletion of the AMPK\u03b12 Subunit Alters Monocyte Protein Expression and Atherogenesis"],"prefix":"10.3390","volume":"20","author":[{"given":"Beate","family":"Fisslthaler","sequence":"first","affiliation":[{"name":"Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany"},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RhineMain, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Zippel","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Randa","family":"Abdel Malik","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fredy","family":"Delgado Lagos","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany"},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RhineMain, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1811-4562","authenticated-orcid":false,"given":"Sven","family":"Zukunft","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany"},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RhineMain, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janina","family":"Thoele","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany"},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RhineMain, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5120-7931","authenticated-orcid":false,"given":"Daniel","family":"Siuda","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany"},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RhineMain, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Soehnlein","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, 80336 Munich, Germany"},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany"},{"name":"Department of Physiology and Pharmacology and Department of Medicine, Karolinska Institute, 17177 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilka","family":"Wittig","sequence":"additional","affiliation":[{"name":"German Center of Cardiovascular Research (DZHK), Partner site RhineMain, 60596 Frankfurt am Main, Germany"},{"name":"Functional Proteomics, SFB 815 Core Unit, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana","family":"Heidler","sequence":"additional","affiliation":[{"name":"German Center of Cardiovascular Research (DZHK), Partner site RhineMain, 60596 Frankfurt am Main, Germany"},{"name":"Functional Proteomics, SFB 815 Core Unit, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7529-1952","authenticated-orcid":false,"given":"Andreas","family":"Weigert","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry I, Goethe-University Frankfurt, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1881-3635","authenticated-orcid":false,"given":"Ingrid","family":"Fleming","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany"},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RhineMain, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1111\/febs.13698","article-title":"AMP-activated protein kinase: A cellular energy sensor that comes in 12 flavours","volume":"283","author":"Ross","year":"2016","journal-title":"FEBS J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.12688\/f1000research.11960.1","article-title":"AMP-activated protein kinase-not just an energy sensor","volume":"6","author":"Hardie","year":"2017","journal-title":"F1000Research"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3667","DOI":"10.1016\/j.febslet.2010.07.041","article-title":"Maintenance of red blood cell integrity by AMP-activated protein kinase \u03b11 catalytic subunit","volume":"584","author":"Foretz","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"19976","DOI":"10.1074\/jbc.M110.102467","article-title":"AMPK\u03b11 deletion shortens erythrocyte life span in mice","volume":"285","author":"Wang","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1172\/JCI16567","article-title":"The AMP-activated protein kinase \u03b12 catalytic subunit controls whole-body insulin sensitivity","volume":"111","author":"Viollet","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1042\/bst0310216","article-title":"Physiological role of AMP-activated protein kinase (AMPK): Insights from knockout mouse models","volume":"31","author":"Viollet","year":"2003","journal-title":"Biochem. Soc. Trans."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1161\/CIRCRESAHA.117.309633","article-title":"AMP-Activated protein kinase: An ubiquitous signaling pathway with key roles in the cardiovascular system","volume":"120","author":"Salt","year":"2017","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"31629","DOI":"10.1074\/jbc.M212831200","article-title":"Direct activation of AMP-activated protein kinase stimulates nitric oxide synthesis in human aortic endothelial cells","volume":"278","author":"Morrow","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10638","DOI":"10.1074\/jbc.M110.108688","article-title":"Activation of AMP-activated protein kinase by vascular endothelial growth factor mediates endothelial angiogenesis independent of nitric-oxide synthase","volume":"285","author":"Stahmann","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15346","DOI":"10.1074\/jbc.M110.102491","article-title":"Activation of the AMP-activated protein kinase \u03b11 alleviates endothelial cell apoptosis by increasing the expression of anti-apoptotic proteins BCL-2 and survivin","volume":"285","author":"Liu","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.1161\/ATVBAHA.113.301848","article-title":"Transforming growth factor-\u03b2-activated kinase 1 regulates angiogenesis via AMP-activated protein kinase-\u03b11 and redox balance in endothelial cells","volume":"33","author":"Zippel","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1161\/CIRCRESAHA.109.212530","article-title":"AMPKa2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo. Role of 26S proteasomes","volume":"106","author":"Wang","year":"2010","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bess, E., Fisslthaler, B., Fr\u00f6mel, T., and Fleming, I. (2011). Nitric oxide-induced activation of the AMP-activated protein kinase \u03b12 subunit attenuates I\u03baB kinase activity and inflammatory responses in endothelial cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020848"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1189\/jlb.0313157","article-title":"AMPK\u03b11 deficiency amplifies proinflammatory myeloid APC activity and CD40 signaling","volume":"94","author":"Carroll","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8633","DOI":"10.4049\/jimmunol.181.12.8633","article-title":"Adenosine 5-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype","volume":"181","author":"Sag","year":"2008","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"584","DOI":"10.4049\/jimmunol.1401024","article-title":"Adenosine 5-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages","volume":"194","author":"Zhu","year":"2015","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s00395-010-0137-9","article-title":"Adipocyte-derived lipids increase angiotensin-converting enzyme (ACE) expression and modulate macrophage phenotype","volume":"106","author":"Kohlstedt","year":"2011","journal-title":"Basic Res. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1161\/CIRCRESAHA.116.309937","article-title":"AMP-activated protein kinase \u03b12 in neutrophils regulates hypoxia-inducible factor-1\u03b1 and a network of proteins affecting metabolism and vascular repair after ischemia","volume":"120","author":"Zippel","year":"2017","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/978-94-007-4525-4_5","article-title":"Metabolic aspects of epigenome: Coupling of S-adenosylmethionine synthesis and gene regulation on chromatin by SAMIT module","volume":"61","author":"Igarashi","year":"2013","journal-title":"Epigenetics Dev. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/j.1432-1033.1989.tb15186.x","article-title":"Purification and characterization of the AMP-activated protein kinase. Copurification of acetyl-CoA carboxylase kinase and 3-hydroxy-3-methylglutaryl-CoA reductase kinase activities","volume":"186","author":"Carling","year":"1989","journal-title":"Eur. J. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e12","DOI":"10.1161\/01.RES.0000257747.74358.1c","article-title":"Fluid shear stress and NO decrease the activity of the hydroxy-methylglutaryl coenzyme A reductase in endothelial cells via the AMP-activated protein kinase and FoxO1","volume":"100","author":"Fisslthaler","year":"2007","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"H1535","DOI":"10.1152\/ajpheart.00510.2009","article-title":"Partial carotid ligation is a model of acutely induced disturbed flow, leading to rapid endothelial dysfunction and atherosclerosis","volume":"297","author":"Nam","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Cui, S., Li, W., Lv, X., Wang, P., Gao, Y., and Huang, G. (2017). Folic acid supplementation delays atherosclerotic lesion development by modulating Mcp1 and Vegf DNA methylation levels in vivo and in vitro. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18050990"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"eaaf7478","DOI":"10.1126\/scisignal.aaf7478","article-title":"AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1","volume":"10","author":"Marin","year":"2017","journal-title":"Sci. Signal"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3160","DOI":"10.1016\/j.ijcard.2013.07.150","article-title":"An overview of the crosstalk between inflammatory processes and metabolic dysregulation during diabetic cardiomyopathy","volume":"168","author":"Palomer","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4334","DOI":"10.1172\/JCI81676","article-title":"MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis","volume":"125","author":"Ouimet","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1016\/j.celrep.2017.10.023","article-title":"Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis","volume":"21","author":"Price","year":"2017","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1096\/fj.04-3496fje","article-title":"Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils","volume":"19","author":"Ohki","year":"2005","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1161\/CIRCRESAHA.112.265868","article-title":"Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice","volume":"110","author":"Drechsler","year":"2012","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1161\/CIRCRESAHA.112.300666","article-title":"Neutrophil-derived cathelicidin promotes adhesion of classical monocytes","volume":"112","author":"Wantha","year":"2013","journal-title":"Circ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1161\/ATVBAHA.116.307743","article-title":"AMP-Activated protein kinase \u03b11 in macrophages promotes collateral remodeling and arteriogenesis in mice in vivo","volume":"36","author":"Zhu","year":"2016","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1161\/CIRCULATIONAHA.109.900928","article-title":"Reduction of AMP-activated protein kinase \u03b12 increases endoplasmic reticulum stress and atherosclerosis in vivo","volume":"121","author":"Dong","year":"2010","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1161\/CIRCRESAHA.116.308689","article-title":"AMP-Activated protein kinase alpha 2 deletion induces VSMC phenotypic switching and reduces features of atherosclerotic plaque stability","volume":"119","author":"Ding","year":"2016","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1161\/CIRCRESAHA.116.308301","article-title":"Ablation of adenosine monophosphate-activated protein kinase \u03b11 in vascular smooth muscle cells promotes diet-induced atherosclerotic calcification in vivo","volume":"119","author":"Cai","year":"2016","journal-title":"Circ. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7888","DOI":"10.1074\/jbc.M117.779447","article-title":"AMP-activated protein kinase \u03b11 promotes atherogenesis by increasing monocyte-to-macrophage differentiation","volume":"292","author":"Zhang","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1161\/CIRCRESAHA.113.301282","article-title":"AMP-activated protein kinase regulates endothelial cell angiotensin-converting enzyme expression via p53 and the post-transcriptional regulation of microRNA-143\/145","volume":"112","author":"Kohlstedt","year":"2013","journal-title":"Circ. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Gongol, B., Sari, I., Bryant, T., Rosete, G., and Marin, T. (2018). AMPK: An epigenetic landscape modulator. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103238"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4103","DOI":"10.1242\/jcs.02541","article-title":"Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells","volume":"118","author":"Fleming","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1084\/jem.20052205","article-title":"Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent","volume":"203","author":"Galkina","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nmeth.1322","article-title":"Universal sample preparation method for proteome analysis","volume":"6","author":"Wisniewski","year":"2009","journal-title":"Nat. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1038\/nprot.2007.261","article-title":"Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips","volume":"2","author":"Rappsilber","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1038\/nprot.2016.136","article-title":"The MaxQuant computational platform for mass spectrometry-based shotgun proteomics","volume":"11","author":"Tyanova","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nmeth.3901","article-title":"The Perseus computational platform for comprehensive analysis of (prote)omics data","volume":"13","author":"Tyanova","year":"2016","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/12\/3005\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:59:47Z","timestamp":1760187587000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/12\/3005"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,19]]},"references-count":43,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["ijms20123005"],"URL":"https:\/\/doi.org\/10.3390\/ijms20123005","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,19]]}}}