{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T14:24:49Z","timestamp":1778768689132,"version":"3.51.4"},"reference-count":53,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T00:00:00Z","timestamp":1593993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Gene Therapy Research Program, GTRP 1053 and by the Nebraska Redox Biology Center, Lincoln NE (P30GM103335) and King Abdulaziz City for Science &amp; Technology (12-MED2797-46).","award":["12-MED2797-46)"],"award-info":[{"award-number":["12-MED2797-46)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Accumulation of methylglyoxal (MG) arising from downregulation of its primary degrading enzyme glyoxalase-1 (Glo1) is an underlying cause of diabetic cardiomyopathy (DC). This study investigated if expressing Glo1 in rat hearts shortly after the onset of Type 1 diabetes mellitus (T1DM) would blunt the development of DC employing the streptozotocin-induced T1DM rat model, an adeno-associated virus containing Glo1 driven by the endothelin-1 promoter (AAV2\/9-Endo-Glo1), echocardiography, video edge, confocal imaging, and biochemical\/histopathological assays. After eight weeks of T1DM, rats developed DC characterized by a decreased E:A ratio, fractional shortening, and ejection fraction, and increased isovolumetric relaxation time, E: e\u2019 ratio, and circumferential and longitudinal strains. Evoked Ca2+ transients and contractile kinetics were also impaired in ventricular myocytes. Hearts from eight weeks T1DM rats had lower Glo1 and GSH levels, elevated carbonyl\/oxidative stress, microvascular leakage, inflammation, and fibrosis. A single injection of AAV2\/9 Endo-Glo1 (1.7 \u00d7 1012 viron particles\/kg) one week after onset of T1DM, potentiated GSH, and blunted MG accumulation, carbonyl\/oxidative stress, microvascular leakage, inflammation, fibrosis, and impairments in cardiac and myocyte functions that develop after eight weeks of T1DM. These new data indicate that preventing Glo1 downregulation by administering AAV2\/9-Endo-Glo1 to rats one week after the onset of T1DM, blunted the DC that develops after eight weeks of diabetes by attenuating carbonyl\/oxidative stresses, microvascular leakage, inflammation, and fibrosis.<\/jats:p>","DOI":"10.3390\/antiox9070592","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T11:07:42Z","timestamp":1594033662000},"page":"592","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Adeno-Associated Viral Transfer of Glyoxalase-1 Blunts Carbonyl and Oxidative Stresses in Hearts of Type 1 Diabetic Rats"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0788-6919","authenticated-orcid":false,"given":"Fadhel A.","family":"Alomar","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdullah","family":"Al-Rubaish","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fahad","family":"Al-Muhanna","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amein K.","family":"Al-Ali","sequence":"additional","affiliation":[{"name":"Institute for Research and Medical Consultation, Imam Abdulrahman bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JoEllyn","family":"McMillan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"},{"name":"Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaipaul","family":"Singh","sequence":"additional","affiliation":[{"name":"College of Science and Technology, University of Central Lancashire, Preton PR1 2HE, England, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keshore R.","family":"Bidasee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"},{"name":"Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA"},{"name":"Nebraska Redox Biology Center, Lincoln, NE 68588-0662, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/0002-9149(72)90595-4","article-title":"New type of cardiomyopathy associated with diabetic glomerulosclerosis","volume":"30","author":"Rubler","year":"1972","journal-title":"Am. J. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"266","DOI":"10.4070\/kcj.2015.45.4.266","article-title":"Diabetic Cardiomyopathy; Summary of 41 Years","volume":"45","author":"Yilmaz","year":"2015","journal-title":"Korean Circ. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1007\/s00125-014-3171-6","article-title":"Molecular mechanisms of diabetic cardiomyopathy","volume":"57","author":"Bugger","year":"2014","journal-title":"Diabetologia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1161\/CIRCRESAHA.116.306923","article-title":"Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes","volume":"118","author":"Shah","year":"2016","journal-title":"Circ. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s11010-013-1861-x","article-title":"Conundrum of pathogenesis of diabetic cardiomyopathy: Role of vascular endothelial dysfunction, reactive oxygen species, and mitochondria","volume":"386","author":"Joshi","year":"2014","journal-title":"Mol. Cell. Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1139\/Y10-016","article-title":"Oxidative stress: a key contributor to diabetic cardiomyopathy","volume":"88","author":"Khullar","year":"2010","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"33","DOI":"10.4093\/dmj.2019.0185","article-title":"Mitochondrial Mechanisms in Diabetic Cardiomyopathy","volume":"44","author":"Gollmer","year":"2020","journal-title":"Diabetes Metab. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/978-981-15-1671-9_10","article-title":"Role of Non-coding RNA in Diabetic Cardiomyopathy","volume":"1229","author":"Xia","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1159\/000057403","article-title":"Renin-angiotensin-aldosterone-kinin system influences on diabetic vascular disease and cardiomyopathy","volume":"24","author":"Flack","year":"1998","journal-title":"Miner. Electrolyte Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3389\/fcvm.2018.00028","article-title":"LncRNAs: Proverbial Genomic \u201cJunk\u201d or Key Epigenetic Regulators During Cardiac Fibrosis in Diabetes?","volume":"5","author":"Biswas","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"C1244","DOI":"10.1152\/ajpcell.00137.2012","article-title":"miR-141 as a regulator of the mitochondrial phosphate carrier (Slc25a3) in the type 1 diabetic heart","volume":"303","author":"Baseler","year":"2012","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1093\/eurheartj\/ehv599","article-title":"MicroRNA profiling unveils hyperglycaemic memory in the diabetic heart","volume":"37","author":"Costantino","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1016\/j.bbamcr.2011.01.014","article-title":"Mitochondrial dysfunction in diabetic cardiomyopathy","volume":"1813","author":"Duncan","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_14","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":"ref_15","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.2337\/db15-0568","article-title":"Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the Development of Diabetic Cardiomyopathy","volume":"65","author":"Vulesevic","year":"2016","journal-title":"Diabetes"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1042\/BST20130254","article-title":"Reducing methylglyoxal as a therapeutic target for diabetic heart disease","volume":"42","author":"Vulesevic","year":"2014","journal-title":"Biochem. Soc. Trans."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1124\/mol.112.078352","article-title":"Carbonylation induces heterogeneity in cardiac ryanodine receptor function in diabetes mellitus","volume":"82","author":"Shao","year":"2012","journal-title":"Mol. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"947","DOI":"10.2337\/db10-1145","article-title":"Carbonylation contributes to SERCA2a activity loss and diastolic dysfunction in a rat model of type 1 diabetes","volume":"60","author":"Shao","year":"2011","journal-title":"Diabetes"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Antognelli, C., and Talesa, V.N. (2018). Glyoxalases in Urological Malignancies. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020415"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Nigro, C., Leone, A., Raciti, G.A., Longo, M., Mirra, P., Formisano, P., Beguinot, F., and Miele, C. (2017). Methylglyoxal-Glyoxalase 1 Balance: The Root of Vascular Damage. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18010188"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj2690001","article-title":"The glyoxalase system: New developments towards functional characterization of a metabolic pathway fundamental to biological life","volume":"269","author":"Thornalley","year":"1990","journal-title":"Biochem. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1042\/BJ20111648","article-title":"Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defense against dicarbonyl glycation","volume":"443","author":"Xue","year":"2012","journal-title":"Biochem. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"539","DOI":"10.3892\/ijmm.2017.3018","article-title":"Deoxyactein protects pancreatic beta-cells against methylglyoxal-induced oxidative cell damage by the upregulation of mitochondrial biogenesis","volume":"40","author":"Suh","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3307","DOI":"10.1111\/bph.13617","article-title":"Smooth muscle-generated methylglyoxal impairs endothelial cell-mediated vasodilatation of cerebral micro-vessels in type 1 diabetic rats","volume":"17","author":"Alomar","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.lfs.2016.02.060","article-title":"Methylglyoxal activates NF-kappaB nuclear translocation and induces COX-2 expression via a p38-dependent pathway in synovial cells","volume":"149","author":"Lin","year":"2016","journal-title":"Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"216512","DOI":"10.1155\/2012\/216512","article-title":"Prevention of diabetic complications by activation of Nrf2: Diabetic cardiomyopathy and nephropathy","volume":"2012","author":"Li","year":"2012","journal-title":"Exp. Diabetes Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"311","DOI":"10.2174\/1566523054065066","article-title":"Adeno-associated viral vectors for clinical gene transfer studies","volume":"5","author":"Snyder","year":"2005","journal-title":"Curr. Gene Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1097\/HCO.0000000000000159","article-title":"Adeno-associated virus-mediated gene therapy in cardiovascular disease","volume":"30","author":"Hammoudi","year":"2015","journal-title":"Curr. Opin. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1016\/j.jtcvs.2014.05.070","article-title":"Safety and efficacy of high dose adeno-associated virus 9 encoding sarcoplasmic reticulum Ca2+ adenosine triphosphatase delivered by molecular cardiac surgery with recirculating delivery in ovine ischemic cardiomyopathy","volume":"148","author":"Katz","year":"2014","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1089\/hum.2008.123","article-title":"Adeno-associated virus (AAV) serotype 9 provides global cardiac gene transfer superior to AAV1, AAV6, AAV7, and AAV8 in the mouse and rat","volume":"19","author":"Bish","year":"2008","journal-title":"Hum. Gene Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1089\/hum.2012.235","article-title":"Recombinant AAV9-TLK1B administration ameliorates fractionated radiation-induced xerostomia","volume":"24","author":"Dayton","year":"2013","journal-title":"Hum. Gene Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/S0891-5849(02)00957-7","article-title":"Homocysteine decreases endothelin-1 expression by interfering with the AP-1 signaling pathway","volume":"33","author":"Drunat","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.yjmcc.2017.10.006","article-title":"Echocardiographic evaluation of diastolic function in mouse models of heart disease","volume":"114","author":"Schnelle","year":"2018","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9746","DOI":"10.1038\/s41598-020-65943-9","article-title":"HIV-1-Associated Left Ventricular Cardiac Dysfunction in Humanized Mice","volume":"10","author":"Dash","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s11010-013-1558-1","article-title":"Malondialdehyde and 4-hydroxynonenal adducts are not formed on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) in diabetes","volume":"376","author":"Moore","year":"2013","journal-title":"Mol. Cell. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s10741-013-9384-9","article-title":"Reactive carbonyl species and their roles in sarcoplasmic reticulum Ca2+ cycling defect in the diabetic heart","volume":"19","author":"Tian","year":"2014","journal-title":"Heart Fail. Rev."},{"key":"ref_37","unstructured":"(2020, March 23). Image Processing and Analysis in Java, Available online: http:\/\/rsbweb.nih.gov\/ij\/."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/j.clinbiochem.2004.05.024","article-title":"Preparation, and quantification of methylglyoxal in human plasma using reverse-phase high-performance liquid chromatography","volume":"37","author":"Nemet","year":"2004","journal-title":"Clin. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1038\/nm.4328","article-title":"Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction","volume":"23","author":"Qi","year":"2017","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1074\/jbc.M113.505784","article-title":"A glutathione-independent glyoxalase of the DJ-1 superfamily plays an important role in managing metabolically generated methylglyoxal in Candida albicans","volume":"289","author":"Hasim","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/S0076-6879(85)13062-4","article-title":"Glutathione reductase","volume":"113","author":"Carlberg","year":"1995","journal-title":"Methods Enzymol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0076-6879(85)13050-8","article-title":"Glutathione synthesis: \u03b3-glutamylcysteine synthetase from rat kidney","volume":"113","author":"Seelig","year":"1995","journal-title":"Methods Enzymol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1124\/mol.60.6.1356","article-title":"Ryanodine receptor dysfunction in hearts of streptozotocin-induced diabetic rats","volume":"60","author":"Bidasee","year":"2001","journal-title":"Mol. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1124\/jpet.102.046201","article-title":"Streptozotocin-induced diabetes increases disulfide bond formation on cardiac ryanodine receptor (RyR2)","volume":"305","author":"Bidasee","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1056\/NEJMoa1310799","article-title":"Changes in diabetes-related complications in the United States, 1990\u20132010","volume":"370","author":"Gregg","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/S0891-5849(99)00176-8","article-title":"Biologic and pharmacologic regulation of mammalian glutathione synthesis","volume":"27","author":"Griffith","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"H1619","DOI":"10.1152\/ajpheart.00140.2006","article-title":"Insulin regulation of glutathione and contractile phenotype in diabetic rat ventricular myocytes","volume":"292","author":"Li","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mam.2008.08.006","article-title":"Glutathione: Overview of its protective roles, measurement, and biosynthesis","volume":"30","author":"Forman","year":"2009","journal-title":"Mol. Asp. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.mehy.2013.08.034","article-title":"A proposed mechanism for exercise attenuated methylglyoxal accumulation: Activation of the ARE-Nrf pathway and increased glutathione biosynthesis","volume":"81","author":"Dieter","year":"2013","journal-title":"Med. Hypotheses"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5287","DOI":"10.1167\/iovs.03-0573","article-title":"Methylglyoxal-derived hydroimidazolone advanced glycation end-products of human lens proteins","volume":"44","author":"Ahmed","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1042\/bj3030069","article-title":"Inhibition of electron flow through complex I of the mitochondrial respiratory chain of Ehrlich ascites carcinoma cells by methylglyoxal","volume":"303","author":"Ray","year":"1994","journal-title":"Biochem. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1016\/j.bcp.2009.02.024","article-title":"Methylglyoxal-induced mitochondrial dysfunction in vascular smooth muscle cells","volume":"77","author":"Wang","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"H1206","DOI":"10.1152\/ajpheart.00376.2005","article-title":"Homocysteine causes cerebrovascular leakage in mice","volume":"290","author":"Lominadze","year":"2006","journal-title":"Am. J. Physiol. Heart Circ. Physiol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/7\/592\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:48:03Z","timestamp":1760176083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/7\/592"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,6]]},"references-count":53,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["antiox9070592"],"URL":"https:\/\/doi.org\/10.3390\/antiox9070592","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,6]]}}}