{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:48:52Z","timestamp":1789760932365,"version":"4.0.1"},"reference-count":51,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T00:00:00Z","timestamp":1631577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM115973"],"award-info":[{"award-number":["R01 GM115973"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32 GM08478"],"award-info":[{"award-number":["T32 GM08478"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["P30 DK078392"],"award-info":[{"award-number":["P30 DK078392"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mesenteric ischemia and reperfusion (I\/R) injury can ensue from a variety of vascular diseases and represents a major cause of morbidity and mortality in intensive care units. It causes an inflammatory response associated with local gut dysfunction and remote organ injury. Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of metabolic homeostasis. The catalytic \u03b11 subunit is highly expressed in the intestine and vascular system. In loss-of-function studies, we investigated the biological role of AMPK\u03b11 in affecting the gastrointestinal barrier function. Male knock-out (KO) mice with a systemic deficiency of AMPK\u03b11 and wild-type (WT) mice were subjected to a 30 min occlusion of the superior mesenteric artery. Four hours after reperfusion, AMPK\u03b11 KO mice exhibited exaggerated histological gut injury and impairment of intestinal permeability associated with marked tissue lipid peroxidation and a lower apical expression of the junction proteins occludin and E-cadherin when compared to WT mice. Lung injury with neutrophil sequestration was higher in AMPK\u03b11 KO mice than WT mice and paralleled with higher plasma levels of syndecan-1, a biomarker of endothelial injury. Thus, the data demonstrate that AMPK\u03b11 is an important requisite for epithelial and endothelial integrity and has a protective role in remote organ injury after acute ischemic events.<\/jats:p>","DOI":"10.3390\/ijms22189911","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T21:47:21Z","timestamp":1631656041000},"page":"9911","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Deficiency of AMPK\u03b11 Exacerbates Intestinal Injury and Remote Acute Lung Injury in Mesenteric Ischemia and Reperfusion in Mice"],"prefix":"10.3390","volume":"22","author":[{"given":"Hannah V.","family":"Hayes","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Wolfe","sequence":"additional","affiliation":[{"name":"Division of Critical Care Medicine, Cincinnati Children\u2019s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Division of Critical Care Medicine, Cincinnati Children\u2019s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick C.","family":"Levinsky","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Piraino","sequence":"additional","affiliation":[{"name":"Division of Critical Care Medicine, Cincinnati Children\u2019s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0152-700X","authenticated-orcid":false,"given":"Basilia","family":"Zingarelli","sequence":"additional","affiliation":[{"name":"Division of Critical Care Medicine, Cincinnati Children\u2019s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"G187","DOI":"10.1152\/ajpgi.90595.2008","article-title":"Intestinal ischemia-reperfusion injury: Reversible and irreversible damage imaged in vivo","volume":"297","author":"Guan","year":"2009","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1056\/NEJMra1503884","article-title":"Mesenteric Ischemia","volume":"374","author":"Clair","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s00423-010-0727-x","article-title":"Intestinal ischemia\/reperfusion: Microcirculatory pathology and functional consequences","volume":"396","author":"Vollmar","year":"2011","journal-title":"Langenbeck\u2019s Arch. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1056\/NEJMoa050333","article-title":"Incidence and outcomes of acute lung injury","volume":"353","author":"Rubenfeld","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"a029181","DOI":"10.1101\/cshperspect.a029181","article-title":"Cell-cell junctions organize structural and signaling networks","volume":"10","author":"Garcia","year":"2018","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/nri3608","article-title":"Intestinal epithelial cells: Regulators of barrier function and immune homeostasis","volume":"14","author":"Peterson","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/nri2653","article-title":"Intestinal mucosal barrier function in health and disease","volume":"9","author":"Turner","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1146\/annurev.pathol.4.110807.092135","article-title":"Epithelial barriers in homeostasis and disease","volume":"5","author":"Marchiando","year":"2010","journal-title":"Annu. Rev. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nrm3311","article-title":"AMPK: A nutrient and energy sensor that maintains energy homeostasis","volume":"13","author":"Hardie","year":"2012","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.cmet.2015.05.005","article-title":"Beyond energy homeostasis: The expanding role of AMP-activated protein kinase in regulating metabolism","volume":"21","author":"Carling","year":"2015","journal-title":"Cell Metab."},{"key":"ref_11","first-page":"589","article-title":"Different expression of the catalytic alpha subunits of the AMP activated protein kinase-an immunohistochemical study in human tissue","volume":"26","author":"Quentin","year":"2011","journal-title":"Histol. Histopath."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1210\/en.2013-1750","article-title":"AMPK in the small intestine in normal and pathophysiological conditions","volume":"155","author":"Harmel","year":"2014","journal-title":"Endocrinology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1165\/rcmb.2016-0118OC","article-title":"Age-dependent changes in AMPK metabolic pathways in the lung in a mouse model of hemorrhagic shock","volume":"56","author":"Klingbeil","year":"2017","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1097\/SHK.0000000000000730","article-title":"The AMPK activator AICAR ameliorates age-dependent myocardial injury in murine hemorrhagic shock","volume":"47","author":"Matsiukevich","year":"2017","journal-title":"Shock"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2680","DOI":"10.1016\/j.bbadis.2017.05.027","article-title":"Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock","volume":"1863","author":"Matsiukevich","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1097\/SHK.0000000000000984","article-title":"Metformin exerts beneficial effects in hemorrhagic shock in an AMPK\u03b11-independent manner","volume":"49","author":"Kim","year":"2018","journal-title":"Shock"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.freeradbiomed.2019.02.031","article-title":"Reactive species-induced microvascular dysfunction in ischemia\/reperfusion","volume":"135","author":"Yu","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/j.ajpath.2019.11.016","article-title":"Endothelial glycocalyx impairment in disease: Focus on hyaluronan shedding","volume":"190","author":"Flamion","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.tem.2015.05.010","article-title":"AMPK: Energy sensor and survival mechanism in the ischemic heart","volume":"26","author":"Qi","year":"2015","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1172\/JCI19297","article-title":"AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury","volume":"114","author":"Russell","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s10557-010-6222-3","article-title":"Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction","volume":"24","author":"Paiva","year":"2010","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"H3136","DOI":"10.1152\/ajpheart.00683.2006","article-title":"Dual cardiac contractile effects of the \u03b12-AMPK deletion in low-flow ischemia and reperfusion","volume":"292","author":"Carvajal","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"F731","DOI":"10.1152\/ajprenal.00541.2015","article-title":"Preconditioning mice with activators of AMPK ameliorates ischemic acute kidney injury in vivo","volume":"311","author":"Lieberthal","year":"2016","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101575","DOI":"10.1016\/j.redox.2020.101575","article-title":"Activation of the AMP-related kinase (AMPK) induces renal vasodilatation and downregulates Nox-derived reactive oxygen species (ROS) generation","volume":"34","author":"Contreras","year":"2020","journal-title":"Redox Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1016\/j.freeradbiomed.2012.01.025","article-title":"Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems","volume":"52","author":"Song","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1042\/BJ20090613","article-title":"AMPK\u03b11 regulates the antioxidant status of vascular endothelial cells","volume":"421","author":"Colombo","year":"2009","journal-title":"Biochem. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/hr.2008.25","article-title":"A new constitutively active mutant of AMP-activated protein kinase inhibits anoxia-induced apoptosis of vascular endothelial cell","volume":"32","author":"Nagata","year":"2009","journal-title":"Hypertension Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1096\/fj.201700576R","article-title":"Autophagy and mitochondrial biogenesis impairment contributes to age-dependent liver injury in experimental sepsis: Dysregulation of AMP-activated protein kinase pathway","volume":"32","author":"Inata","year":"2018","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Serino, M., Waget, A., Marsollier, N., Masseboeuf, M., Payros, G., Kabani, C., Denom, J., Lacombe, A., Thiers, J.C., and Negre-Salvayre, A. (2011). Lipid-induced peroxidation in the intestine is involved in glucose homeostasis imbalance in mice. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021184"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1136\/gutjnl-2018-316906","article-title":"Tight junction proteins in gastrointestinal and liver disease","volume":"68","author":"Zeisel","year":"2019","journal-title":"Gut"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrm3802","article-title":"Dynamic contacts: Rearranging adherens junctions to drive epithelial remodelling","volume":"15","author":"Takeichi","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1097\/00024382-200303000-00006","article-title":"Proinflammatory cytokines cause NO*-dependent and -independent changes in expression and localization of tight junction proteins in intestinal epithelial cells","volume":"19","author":"Han","year":"2003","journal-title":"Shock"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1096\/fj.04-3260com","article-title":"Interferon-gamma induces internalization of epithelial tight junction proteins via a macropinocytosis-like process","volume":"19","author":"Bruewer","year":"2005","journal-title":"FASEB J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/nyas.13346","article-title":"Endocytosis of tight junction proteins and the regulation of degradation and recycling","volume":"1397","author":"Stamatovic","year":"2017","journal-title":"Ann. N.Y. Acad. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/cdd.2017.14","article-title":"AMPK improves gut epithelial differentiation and barrier function via regulating Cdx2 expression","volume":"24","author":"Sun","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Olivier, S., Leclerc, J., Grenier, A., Foretz, M., Tamburini, J., and Viollet, B. (2019). AMPK activation promotes tight junction assembly in intestinal epithelial Caco-2 cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205171"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"F847","DOI":"10.1152\/ajprenal.2000.278.5.F847","article-title":"Selective degradation of E-cadherin and dissolution of E-cadherin-catenin complexes in epithelial ischemia","volume":"278","author":"Bush","year":"2000","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1042\/BJ20110587","article-title":"Protein kinase Czeta phosphorylates occludin and promotes assembly of epithelial tight junctions","volume":"437","author":"Jain","year":"2011","journal-title":"Biochem. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1073\/pnas.0802741106","article-title":"PKC eta regulates occludin phosphorylation and epithelial tight junction integrity","volume":"106","author":"Suzuki","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1080\/09168451.2014.951027","article-title":"Theaflavins enhance intestinal barrier of Caco-2 Cell monolayers through the expression of AMP-activated protein kinase-mediated Occludin, Claudin-1, and ZO-1","volume":"79","author":"Park","year":"2015","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3945\/jn.115.224857","article-title":"L-glutamine enhances tight junction integrity by activating CaMK kinase 2-AMP-activated protein kinase signaling in intestinal porcine epithelial cells","volume":"146","author":"Wang","year":"2016","journal-title":"J. Nutr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/ncb3537","article-title":"Linking E-cadherin mechanotransduction to cell metabolism through force-mediated activation of AMPK","volume":"19","author":"Bays","year":"2017","journal-title":"Nat. Cell. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.ccc.2015.11.004","article-title":"The gut as the motor of multiple organ dysfunction in critical illness","volume":"32","author":"Klingensmith","year":"2016","journal-title":"Crit. Care Clin."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jcrc.2018.06.015","article-title":"Glycocalyx biomarker syndecan-1 is a stronger predictor of respiratory failure in patients with sepsis due to pneumonia, compared to endocan","volume":"47","author":"Smart","year":"2018","journal-title":"J. Crit. Care"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2741\/3229","article-title":"AMPK: Lessons from transgenic and knockout animals","volume":"14","author":"Viollet","year":"2009","journal-title":"Front. Biosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1016\/S0041-1345(00)01238-0","article-title":"An evaluation of methods for grading histologic injury following ischemia\/reperfusion of the small bowel","volume":"32","author":"Quaedackers","year":"2000","journal-title":"Transplant. Proc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"G833","DOI":"10.1152\/ajpgi.00065.2010","article-title":"HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury","volume":"299","author":"Feinman","year":"2010","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Woting, A., and Blaut, M. (2018). Small intestinal permeability and gut-transit time determined with low and high molecular weight Fluorescein Isothiocyanate-Dextrans in C3H Mice. Nutrients, 10.","DOI":"10.3390\/nu10060685"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for lipid peroxides in animal tissue by thiobarbituric acid reaction","volume":"95","author":"Ohkawa","year":"1979","journal-title":"Anal. Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0160-5402(85)90029-4","article-title":"Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium","volume":"14","author":"Mullane","year":"1985","journal-title":"J. Pharmacol. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9911\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:24Z","timestamp":1760166144000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9911"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,14]]},"references-count":51,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22189911"],"URL":"https:\/\/doi.org\/10.3390\/ijms22189911","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,14]]}}}