{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:33:43Z","timestamp":1792154023630,"version":"4.4.0"},"reference-count":42,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T00:00:00Z","timestamp":1595980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["(MOST 102-2320-B-003-001-MY3)"],"award-info":[{"award-number":["(MOST 102-2320-B-003-001-MY3)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Diabetes exacerbates myocardial ischemia\/reperfusion (IR) injury by incompletely understood mechanisms. We explored whether diabetes diminished BAG3\/Bcl-2\/Nrf-2\/HO-1-mediated cardioprotection and overproduced oxidative stress contributing to exaggerated IR injury. Streptozotocin-induced diabetes enhanced hyperglycemia, cardiac NADPH oxidase p22\/p67 expression, malondialdehyde amount and leukocyte infiltration, altered the mesenteric expression of 4-HNE, CaSR, p-eNOS and BAG3 and impaired microvascular reactivity to the vasoconstrictor\/vasodilator by a wire myography. In response to myocardial IR, diabetes further depressed BAG3\/Bcl-2\/Nrf-2\/HO-1 expression, increased cleaved-caspase 3\/poly(ADP-ribose) polymerase (PARP)\/TUNEL-mediated apoptosis and exacerbated IR-induced left ventricular dysfunction characterized by further depressed microcirculation, heart rate, left ventricular systolic pressure and peak rate of pressure increase\/decrease (\u00b1dp\/dt) and elevated left ventricular end-diastolic pressure (LVEDP) and Evans blue-2,3,5-triphenyltetrazolium chloride-stained infarct size in diabetic hearts. Our results implicated diabetes exacerbated IR-induced myocardial dysfunction through downregulated BAG3\/Bcl-2\/Nrf-2\/HO-1 expression, increased p22\/p67\/caspase 3\/PARP\/apoptosis-mediated oxidative injury and impaired microvascular reactivity.<\/jats:p>","DOI":"10.3390\/antiox9080679","type":"journal-article","created":{"date-parts":[[2020,7,30]],"date-time":"2020-07-30T03:36:38Z","timestamp":1596080198000},"page":"679","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Diabetes Upregulates Oxidative Stress and Downregulates Cardiac Protection to Exacerbate Myocardial Ischemia\/Reperfusion Injury in Rats"],"prefix":"10.3390","volume":"9","author":[{"given":"Chen-Yen","family":"Chien","sequence":"first","affiliation":[{"name":"Department of Surgery, Mackay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan"},{"name":"Mackay Junior College of Medicine, Nursing and Management, New Taipei City 11260, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Jui","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Life Science, School of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hsiuan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Life Science, School of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ting","family":"Tsai","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Surgery, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4157-6888","authenticated-orcid":false,"given":"Chih-Yao","family":"Chiang","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Surgery, National Defense Medical Center, Taipei 11490, Taiwan"},{"name":"Division of Cardiovascular Surgery, Heart Center, Cheng Hsin General Hospital, Taipei 11220, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7580-7069","authenticated-orcid":false,"given":"Chiang-Ting","family":"Chien","sequence":"additional","affiliation":[{"name":"Department of Life Science, School of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.jchf.2016.08.001","article-title":"Hypertension, Obesity, Diabetes, and Heart Failure-Free Survival: The Cardiovascular Disease Lifetime Risk Pooling Project","volume":"4","author":"Ahmad","year":"2016","journal-title":"JACC Heart Fail."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1161\/CIR.0000000000000366","article-title":"Executive Summary: Heart Disease and Stroke Statistics\u20142016 Update: A Report From the American Heart Association","volume":"133","author":"Mozaffarian","year":"2016","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1056\/NEJM199807233390404","article-title":"Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction","volume":"339","author":"Haffner","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1161\/CIRCRESAHA.115.307937","article-title":"Coronary artery disease and its risk factors: Leveraging shared genetics to discover novel biology","volume":"118","author":"Quertermous","year":"2016","journal-title":"Circ. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.freeradbiomed.2018.02.021","article-title":"Evaluating the impact of diabetes and diabetic cardiomyopathy rat heart on the outcome of ischemia-reperfusion associated oxidative stress","volume":"118","author":"Mahalakshmi","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_6","first-page":"S81","article-title":"Standards of Medical Care in Diabetes","volume":"42","author":"Lei","year":"2019","journal-title":"Diabetes Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"421","DOI":"10.7326\/0003-4819-141-6-200409210-00007","article-title":"Meta-analysis: Glycosylated hemoglobin and cardiovascular disease in diabetes mellitus","volume":"141","author":"Selvin","year":"2004","journal-title":"Ann. Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1007\/s00125-010-1871-0","article-title":"Dysglycaemia and the risk of acute myocardial infarction in multiple ethnic groups: An analysis of 15,780 patients from the INTERHEART study","volume":"53","author":"Gerstein","year":"2010","journal-title":"Diabetologia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1007\/s00125-005-1858-4","article-title":"HOPE investigators. The relationship between dysglycaemia and cardiovascular and renal risk in diabetic and non-diabetic participants in the HOPE study: A prospective epidemiological analysis","volume":"48","author":"Gerstein","year":"2005","journal-title":"Diabetologia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.1016\/j.bbadis.2013.08.006","article-title":"Endothelial dysfunction\u2014A major mediator of diabetic vascular disease","volume":"1832","author":"Sena","year":"2013","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/414813a","article-title":"Biochemistry and molecular cell biology of diabetic complications","volume":"414","author":"Brownlee","year":"2001","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e90931","DOI":"10.1172\/jci.insight.90931","article-title":"Bcl-2-associated athanogene 3 protects the heart from ischemia\/reperfusion injury","volume":"1","author":"Su","year":"2016","journal-title":"JCI Insight"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/1475-2840-12-133","article-title":"Susceptibility to myocardial ischemia reperfusion injury at early stage of type 1 diabetes in rats","volume":"12","author":"Li","year":"2013","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.freeradbiomed.2013.05.043","article-title":"N-Acetylcysteine and allopurinol up-regulated the Jak\/STAT3 and PI3K\/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes","volume":"63","author":"Wang","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.biocel.2018.10.011","article-title":"Experimental diabetes mellitus exacerbates ischemia\/reperfusion-induced myocardial injury by promoting mitochondrial fission: Role of down-regulation of myocardial Sirt1 and subsequent Akt\/Drp1 interaction","volume":"105","author":"Tao","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108754","DOI":"10.1016\/j.cbi.2019.108754","article-title":"Piceatannol alleviates inflammation and oxidative stress via modulation of the Nrf2\/HO-1 and NF-\u03baB pathways in diabetic cardiomyopathy","volume":"310","author":"Li","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s10741-015-9487-6","article-title":"BAG3: A new player in the heart failure paradigm","volume":"20","author":"Knezevic","year":"2015","journal-title":"Heart Fail. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.4161\/auto.29409","article-title":"BAG3 induces the sequestration of proteasomal clients into cytoplasmic puncta: Implications for a proteasome-to-autophagy switch","volume":"10","author":"Minoia","year":"2014","journal-title":"Autophagy"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.ymgme.2018.01.001","article-title":"Dysregulated autophagy in restrictive cardiomyopathy due to Pro209Leu mutation in BAG3","volume":"123","author":"Rupp","year":"2018","journal-title":"Mol. Genet. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"761","DOI":"10.2353\/ajpath.2006.060250","article-title":"BAG3 deficiency results in fulminant myopathy and early lethality","volume":"169","author":"Homma","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/jcp.25476","article-title":"Evidence for the role of BAG3 in mitochondrial quality control in cardiomyocytes","volume":"232","author":"Tahrir","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2431","DOI":"10.1038\/cddis.2016.321","article-title":"The prosurvival protein BAG3: A new participant in vascular homeostasis","volume":"7","author":"Carrizzo","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1097\/FJC.0b013e31828d0fa3","article-title":"Ca2+-sensing receptor cleavage by calpain partially accounts for altered vascular reactivity in mice fed a high-fat diet","volume":"61","author":"Loot","year":"2013","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bellezza, I., Riuzzi, F., Chiappalupi, S., Arcuri, C., Giambanco, I., Sorci, G., and Donato, R. (2020). Reductive stress in striated muscle cells. Cell. Mol. Life Sci., Accepted.","DOI":"10.1007\/s00018-020-03476-0"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"504693","DOI":"10.1155\/2012\/504693","article-title":"Antioxidant sol-gel improves cutaneous wound healing in streptozotocin-induced diabetic rats","volume":"2012","author":"Lee","year":"2012","journal-title":"Exp. Diabetes Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chen, Y.H., Chiang, C.Y., Chang, T.C., and Chien, C.T. (2020). Multiple Progressive thermopreconditioning improves cardiac ischemia\/reperfusion induced left ventricular contractile dysfunction and structural abnormality in rat. Transplantation, Accepted.","DOI":"10.1097\/TP.0000000000003176"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.jtcvs.2013.12.065","article-title":"Progressive thermopreconditioning attenuates rat cardiac ischemia\/reperfusion injury by mitochondria-mediated antioxidant and antiapoptotic mechanisms","volume":"148","author":"Chien","year":"2014","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1055\/s-0038-1672206","article-title":"Genetic depletion of thromboxane A2\/thromboxane-prostanoid receptor signalling prevents microvascular dysfunction in ischaemia\/reperfusion injury","volume":"118","author":"Chiang","year":"2018","journal-title":"Thromb. Haemost."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1089\/ars.2010.3343","article-title":"Cardioprotection with postconditioning: Loss of efficacy in murine models of type-2 and type-1 diabetes","volume":"14","author":"Przyklenk","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"H727","DOI":"10.1152\/ajpheart.00269.2003","article-title":"Acrolein-induced vasomotor responses of rat aorta","volume":"285","author":"Tsakadze","year":"2003","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1016\/j.athoracsur.2006.01.024","article-title":"Thromboxane receptor stimulation suppresses guanylate cyclase-mediated relaxation of radial arteries","volume":"81","author":"Arshad","year":"2006","journal-title":"Ann. Thorac. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/s12012-013-9213-3","article-title":"Pulmonary cerium dioxide nanoparticle exposure differentially impairs coronary and mesenteric arteriolar reactivity","volume":"13","author":"Minarchick","year":"2013","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"H1183","DOI":"10.1152\/ajpheart.00327.2012","article-title":"Sex differences in mesenteric endothelial function of streptozotocin-induced diabetic rats: A shift in the relative importance of EDRFs","volume":"303","author":"Zhang","year":"2012","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"419","DOI":"10.4097\/kjae.2011.61.5.419","article-title":"Gender difference and change of \u03b11-adrenoceptors in the distal mesenteric arteries of streptozotocin-induced diabetic rats","volume":"61","author":"Park","year":"2011","journal-title":"Korean J. Anesthesiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1161\/01.CIR.94.4.742","article-title":"Endothelin-1-induced release of thromboxane A2 increases the vasoconstrictor effect of endothelin-1 in postischemic reperfused rat hearts","volume":"94","author":"Zaugg","year":"1996","journal-title":"Circulation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/path.4113","article-title":"Oxidative stress and myocardial injury in the diabetic heart","volume":"229","author":"Ansley","year":"2013","journal-title":"J. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.2174\/138161211796391047","article-title":"Nitric oxide and protection against cardiac ischemia","volume":"17","author":"Xia","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.cardiores.2003.11.028","article-title":"Role of clinical pathologies in myocardial injury following ischaemia and reperfusion","volume":"61","author":"Fowler","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1042\/CS20150496","article-title":"Selective inhibition of PTEN preserves ischaemic post-conditioning cardioprotection in STZ-induced Type 1 diabetic rats: Role of the PI3K\/Akt and JAK2\/STAT3 pathways","volume":"130","author":"Xue","year":"2016","journal-title":"Clin. Sci."},{"key":"ref_40","first-page":"4213","article-title":"CCAAT\/enhancer binding protein homologous protein knockdown alleviates hypoxia-induced myocardial injury in rat cardiomyocytes exposed to high glucose","volume":"15","author":"Yang","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/j.1527-3466.2007.00018.x","article-title":"Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: The therapeutic potential of PARP inhibitors","volume":"25","author":"Pacher","year":"2007","journal-title":"Cardiovasc. Drug Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s11010-016-2716-z","article-title":"Nobiletin attenuates cardiac dysfunction, oxidative stress, and inflammatory in streptozotocin: Induced diabetic cardiomyopathy","volume":"417","author":"Zhang","year":"2016","journal-title":"Mol. Cell. Biochem."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/8\/679\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:52:43Z","timestamp":1760176363000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/8\/679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,29]]},"references-count":42,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["antiox9080679"],"URL":"https:\/\/doi.org\/10.3390\/antiox9080679","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,29]]}}}