{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:05:52Z","timestamp":1790960752143,"version":"4.1.0"},"reference-count":50,"publisher":"American Diabetes Association","issue":"6","license":[{"start":{"date-parts":[[2016,12,1]],"date-time":"2016-12-01T00:00:00Z","timestamp":1480550400000},"content-version":"vor","delay-in-days":268,"URL":"http:\/\/www.diabetesjournals.org\/site\/license"}],"funder":[{"DOI":"10.13039\/100004411","name":"Heart & Stroke Foundation of Canada","doi-asserted-by":"publisher","award":["000225"],"award-info":[{"award-number":["000225"]}],"id":[{"id":"10.13039\/100004411","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FRN 125678"],"award-info":[{"award-number":["FRN 125678"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,6,1]]},"abstract":"<jats:p>The mechanisms for the development of diabetic cardiomyopathy remain largely unknown. Methylglyoxal (MG) can accumulate and promote inflammation and vascular damage in diabetes. We examined if overexpression of the MG-metabolizing enzyme glyoxalase 1 (GLO1) in macrophages and the vasculature could reduce MG-induced inflammation and prevent ventricular dysfunction in diabetes. Hyperglycemia increased circulating inflammatory markers in wild-type (WT) but not in GLO1-overexpressing mice. Endothelial cell number was reduced in WT-diabetic hearts compared with nondiabetic controls, whereas GLO1 overexpression preserved capillary density. Neuregulin production, endothelial nitric oxide synthase dimerization, and Bcl-2 expression in endothelial cells was maintained in the hearts of GLO1-diabetic mice and corresponded to less myocardial cell death compared with the WT-diabetic group. Lower receptor for advanced glycation end products and tumor necrosis factor-\u03b1 (TNF-\u03b1) levels were also observed in GLO1-diabetic versus WT-diabetic mice. Over a period of 8 weeks of hyperglycemia, GLO1 overexpression delayed and limited the loss of cardiac function. In vitro, MG and TNF-\u03b1 were shown to synergize in promoting endothelial cell death, which was associated with increased angiopoietin 2 expression and reduced Bcl-2 expression. These results suggest that MG in diabetes increases inflammation, leading to endothelial cell loss. This contributes to the development of diabetic cardiomyopathy and identifies MG-induced endothelial inflammation as a target for therapy.<\/jats:p>","DOI":"10.2337\/db15-0568","type":"journal-article","created":{"date-parts":[[2016,3,9]],"date-time":"2016-03-09T04:43:35Z","timestamp":1457498615000},"page":"1699-1713","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":112,"title":["Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the Development of Diabetic Cardiomyopathy"],"prefix":"10.2337","volume":"65","author":[{"given":"Branka","family":"Vulesevic","sequence":"first","affiliation":[{"name":"Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada"},{"name":"Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"McNeill","sequence":"additional","affiliation":[{"name":"Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdinando","family":"Giacco","sequence":"additional","affiliation":[{"name":"Diabetes Research Center, Departments of Internal Medicine and Pathology, Albert Einstein College of Medicine, Bronx, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay","family":"Maeda","sequence":"additional","affiliation":[{"name":"Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick J.R.","family":"Blackburn","sequence":"additional","affiliation":[{"name":"Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada"},{"name":"Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Brownlee","sequence":"additional","affiliation":[{"name":"Diabetes Research Center, Departments of Internal Medicine and Pathology, Albert Einstein College of Medicine, Bronx, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross W.","family":"Milne","sequence":"additional","affiliation":[{"name":"Diabetes and Atherosclerosis Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik J.","family":"Suuronen","sequence":"additional","affiliation":[{"name":"Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada"},{"name":"Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2016,3,8]]},"reference":[{"key":"2022031300042684000_B1","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1042\/CS20040057","article-title":"Diabetic cardiomyopathy: mechanisms, diagnosis and treatment","volume":"107","author":"Hayat","year":"2004","journal-title":"Clin Sci (Lond)"},{"key":"2022031300042684000_B2","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1161\/01.RES.0000207406.94146.c2","article-title":"Diabetic cardiomyopathy: the search for a unifying hypothesis","volume":"98","author":"Poornima","year":"2006","journal-title":"Circ Res"},{"key":"2022031300042684000_B3","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s11154-010-9131-7","article-title":"Diabetic cardiomyopathy, causes and effects","volume":"11","author":"Boudina","year":"2010","journal-title":"Rev Endocr Metab Disord"},{"key":"2022031300042684000_B4","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1161\/CIRCULATIONAHA.108.835223","article-title":"Molecular insights and therapeutic targets for diabetic endothelial dysfunction","volume":"120","author":"Xu","year":"2009","journal-title":"Circulation"},{"key":"2022031300042684000_B5","first-page":"853","article-title":"Endothelial dysfunction in diabetes mellitus","volume":"3","author":"Hadi","year":"2007","journal-title":"Vasc Health Risk Manag"},{"key":"2022031300042684000_B6","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1161\/CIRCRESAHA.110.223545","article-title":"Oxidative stress and diabetic complications","volume":"107","author":"Giacco","year":"2010","journal-title":"Circ Res"},{"key":"2022031300042684000_B7","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1042\/bst0311343","article-title":"Glyoxalase I--structure, function and a critical role in the enzymatic defence against glycation","volume":"31","author":"Thornalley","year":"2003","journal-title":"Biochem Soc Trans"},{"key":"2022031300042684000_B8","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S0006-2952(99)00132-X","article-title":"Accumulation of \u03b1-oxoaldehydes during oxidative stress: a role in cytotoxicity","volume":"58","author":"Abordo","year":"1999","journal-title":"Biochem Pharmacol"},{"key":"2022031300042684000_B9","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1515\/CCLM.2003.180","article-title":"Glyoxal and methylglyoxal levels in diabetic patients: quantitative determination by a new GC\/MS method","volume":"41","author":"Lapolla","year":"2003","journal-title":"Clin Chem Lab Med"},{"key":"2022031300042684000_B10","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1007\/s00125-010-1677-0","article-title":"Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress","volume":"53","author":"Brouwers","year":"2010","journal-title":"Diabetologia"},{"key":"2022031300042684000_B11","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1515\/jbcpp-2013-0095","article-title":"Methylglyoxal causes endothelial dysfunction: the role of endothelial nitric oxide synthase and AMP-activated protein kinase \u03b1","volume":"25","author":"Turkseven","year":"2014","journal-title":"J Basic Clin Physiol Pharmacol"},{"key":"2022031300042684000_B12","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/nrcardio.2010.35","article-title":"Intensive glycemic control and cardiovascular disease: an update","volume":"7","author":"Brown","year":"2010","journal-title":"Nat Rev Cardiol"},{"key":"2022031300042684000_B13","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1111\/j.1476-5381.2010.01017.x","article-title":"Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose","volume":"161","author":"Dhar","year":"2010","journal-title":"Br J Pharmacol"},{"key":"2022031300042684000_B14","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.phrs.2012.03.004","article-title":"Methylglyoxal promotes oxidative stress and endothelial dysfunction","volume":"65","author":"Sena","year":"2012","journal-title":"Pharmacol Res"},{"key":"2022031300042684000_B15","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1161\/CIRCULATIONAHA.107.690487","article-title":"Role of neuregulin-1\/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure","volume":"116","author":"Lemmens","year":"2007","journal-title":"Circulation"},{"key":"2022031300042684000_B16","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1161\/CIRCULATIONAHA.108.847731","article-title":"Cell communications in the heart","volume":"122","author":"Tirziu","year":"2010","journal-title":"Circulation"},{"key":"2022031300042684000_B17","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/S0735-1097(00)01002-0","article-title":"Congestive heart failure induces endothelial cell apoptosis: protective role of carvedilol","volume":"36","author":"R\u00f6ssig","year":"2000","journal-title":"J Am Coll Cardiol"},{"key":"2022031300042684000_B18","doi-asserted-by":"crossref","first-page":"e12043","DOI":"10.14814\/phy2.12043","article-title":"Differential effects of glyoxalase 1 overexpression on diabetic atherosclerosis and renal dysfunction in streptozotocin-treated, apolipoprotein E-deficient mice","volume":"2","author":"Geoffrion","year":"2014","journal-title":"Physiol Rep"},{"key":"2022031300042684000_B19","doi-asserted-by":"crossref","first-page":"291","DOI":"10.2337\/db13-0316","article-title":"Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice","volume":"63","author":"Giacco","year":"2014","journal-title":"Diabetes"},{"key":"2022031300042684000_B20","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1093\/cvr\/cvt259","article-title":"Glyoxalase-1 overexpression in bone marrow cells reverses defective neovascularization in STZ-induced diabetic mice","volume":"101","author":"Vulesevic","year":"2014","journal-title":"Cardiovasc Res"},{"key":"2022031300042684000_B21","doi-asserted-by":"crossref","first-page":"S70","DOI":"10.1161\/CIRCULATIONAHA.113.007908","article-title":"Hyperglycemia inhibits cardiac stem cell-mediated cardiac repair and angiogenic capacity","volume":"130","author":"Molgat","year":"2014","journal-title":"Circulation"},{"key":"2022031300042684000_B22","doi-asserted-by":"crossref","first-page":"H1829","DOI":"10.1152\/ajpheart.00230.2009","article-title":"eNOS uncoupling and endothelial dysfunction in aged vessels","volume":"297","author":"Yang","year":"2009","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2022031300042684000_B23","doi-asserted-by":"crossref","first-page":"5103","DOI":"10.1242\/dev.02096","article-title":"Retinal ganglion cell-derived sonic hedgehog locally controls proliferation and the timing of RGC development in the embryonic mouse retina","volume":"132","author":"Wang","year":"2005","journal-title":"Development"},{"key":"2022031300042684000_B24","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1002\/jbmr.5650020209","article-title":"Effect of bisphosphonates on proliferation and viability of mouse bone marrow-derived macrophages","volume":"2","author":"Cecchini","year":"1987","journal-title":"J Bone Miner Res"},{"key":"2022031300042684000_B25","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1172\/JCI200524459","article-title":"NO\/redox disequilibrium in the failing heart and cardiovascular system","volume":"115","author":"Hare","year":"2005","journal-title":"J Clin Invest"},{"key":"2022031300042684000_B26","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1161\/CIRCRESAHA.112.267286","article-title":"Neuregulin in cardiovascular development and disease","volume":"111","author":"Odiete","year":"2012","journal-title":"Circ Res"},{"key":"2022031300042684000_B27","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.2741\/1270","article-title":"Endothelial microparticles as markers of endothelial dysfunction","volume":"9","author":"Horstman","year":"2004","journal-title":"Front Biosci"},{"key":"2022031300042684000_B28","doi-asserted-by":"crossref","first-page":"4219","DOI":"10.1161\/01.CIR.96.12.4219","article-title":"Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study","volume":"96","author":"Hwang","year":"1997","journal-title":"Circulation"},{"key":"2022031300042684000_B29","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1136\/hrt.2002.007005","article-title":"Inflammatory mediators in chronic heart failure: an overview","volume":"90","author":"Anker","year":"2004","journal-title":"Heart"},{"key":"2022031300042684000_B30","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0009-8981(03)00003-2","article-title":"Protein carbonyl groups as biomarkers of oxidative stress","volume":"329","author":"Dalle-Donne","year":"2003","journal-title":"Clin Chim Acta"},{"key":"2022031300042684000_B31","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/1475-2840-10-73","article-title":"High glucose-induced apoptosis in human coronary artery endothelial cells involves up-regulation of death receptors","volume":"10","author":"Kageyama","year":"2011","journal-title":"Cardiovasc Diabetol"},{"key":"2022031300042684000_B32","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.bbrc.2008.06.023","article-title":"Telmisartan inhibits methylglyoxal-mediated cell death in human vascular endothelium","volume":"373","author":"Baden","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031300042684000_B33","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1248\/bpb.33.556","article-title":"Buthionine sulfoximine promotes methylglyoxal-induced apoptotic cell death and oxidative stress in endothelial cells","volume":"33","author":"Takahashi","year":"2010","journal-title":"Biol Pharm Bull"},{"key":"2022031300042684000_B34","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1113\/expphysiol.2010.053561","article-title":"Methylglyoxal-induced imbalance in the ratio of vascular endothelial growth factor to angiopoietin 2 secreted by retinal pigment epithelial cells leads to endothelial dysfunction","volume":"95","author":"Bento","year":"2010","journal-title":"Exp Physiol"},{"key":"2022031300042684000_B35","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.yexcr.2008.08.015","article-title":"The role of Neuregulin-1beta\/ErbB signaling in the heart","volume":"315","author":"Pentassuglia","year":"2009","journal-title":"Exp Cell Res"},{"key":"2022031300042684000_B36","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.carpath.2011.12.006","article-title":"Neuregulin-1\/ErbB signaling is impaired in the rat model of diabetic cardiomyopathy","volume":"21","author":"Gui","year":"2012","journal-title":"Cardiovasc Pathol"},{"key":"2022031300042684000_B37","doi-asserted-by":"crossref","first-page":"10930","DOI":"10.1074\/jbc.M707451200","article-title":"Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice","volume":"283","author":"Ceradini","year":"2008","journal-title":"J Biol Chem"},{"key":"2022031300042684000_B38","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1111\/acel.12204","article-title":"Glyoxalase I reduces glycative and oxidative stress and prevents age-related endothelial dysfunction through modulation of endothelial nitric oxide synthase phosphorylation","volume":"13","author":"Jo-Watanabe","year":"2014","journal-title":"Aging Cell"},{"key":"2022031300042684000_B39","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/1475-2840-8-58","article-title":"Elevated plasma levels of TNF-alpha and interleukin-6 in patients with diastolic dysfunction and glucose metabolism disorders","volume":"8","author":"Dinh","year":"2009","journal-title":"Cardiovasc Diabetol"},{"key":"2022031300042684000_B40","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/S0003-9861(02)00599-4","article-title":"Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation","volume":"409","author":"Fan","year":"2003","journal-title":"Arch Biochem Biophys"},{"key":"2022031300042684000_B41","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.pharmthera.2010.05.002","article-title":"TNFalpha in atherosclerosis, myocardial ischemia\/reperfusion and heart failure","volume":"127","author":"Kleinbongard","year":"2010","journal-title":"Pharmacol Ther"},{"key":"2022031300042684000_B42","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.yjmcc.2009.12.013","article-title":"Tumor necrosis factor-alpha produced in cardiomyocytes mediates a predominant myocardial inflammatory response to stretch in early volume overload","volume":"49","author":"Chen","year":"2010","journal-title":"J Mol Cell Cardiol"},{"key":"2022031300042684000_B43","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nm1351","article-title":"Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation","volume":"12","author":"Fiedler","year":"2006","journal-title":"Nat Med"},{"key":"2022031300042684000_B44","doi-asserted-by":"crossref","first-page":"31038","DOI":"10.1074\/jbc.M704703200","article-title":"High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A","volume":"282","author":"Yao","year":"2007","journal-title":"J Biol Chem"},{"key":"2022031300042684000_B45","doi-asserted-by":"crossref","first-page":"3327","DOI":"10.1021\/bi500046t","article-title":"The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs","volume":"53","author":"Xue","year":"2014","journal-title":"Biochemistry"},{"key":"2022031300042684000_B46","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s11897-012-0089-5","article-title":"Receptor for advanced glycation end products (RAGE) and implications for the pathophysiology of heart failure","volume":"9","author":"Ramasamy","year":"2012","journal-title":"Curr Heart Fail Rep"},{"key":"2022031300042684000_B47","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1161\/01.RES.84.5.489","article-title":"Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis","volume":"84","author":"Schmidt","year":"1999","journal-title":"Circ Res"},{"key":"2022031300042684000_B48","doi-asserted-by":"crossref","first-page":"15724","DOI":"10.3390\/ijms140815724","article-title":"Mild oxidative damage in the diabetic rat heart is attenuated by glyoxalase-1 overexpression","volume":"14","author":"Brouwers","year":"2013","journal-title":"Int J Mol Sci"},{"key":"2022031300042684000_B49","doi-asserted-by":"crossref","first-page":"249","DOI":"10.2337\/db09-0801","article-title":"Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands","volume":"59","author":"Yao","year":"2010","journal-title":"Diabetes"},{"key":"2022031300042684000_B50","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1161\/CIRCULATIONAHA.110.942268","article-title":"Molecular pathways underlying cardiac remodeling during pathophysiological stimulation","volume":"122","author":"Kehat","year":"2010","journal-title":"Circulation"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/diabetes.diabetesjournals.org\/syndication\/doi\/10.2337\/db15-0568","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/65\/6\/1699\/582917\/db150568.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/65\/6\/1699\/582917\/db150568.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:47:23Z","timestamp":1667407643000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/65\/6\/1699\/35146\/Methylglyoxal-Induced-Endothelial-Cell-Loss-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,8]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2016,3,8]]},"published-print":{"date-parts":[[2016,6,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db15-0568","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,8]]}}}