{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T02:51:30Z","timestamp":1782269490845,"version":"3.54.5"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,7]],"date-time":"2018-02-07T00:00:00Z","timestamp":1517961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Many studies reported that air pollution particulate matter (PM) exposure was associated with myocardial infarction (MI). Acrolein representing the unsaturated aldehydes, the main component of PM, derives from the incomplete combustion of wood, plastic, fossil fuels and the main constitute of cigarette smoking. However, the effect of acrolein on MI remains not that clear. In the current study, the effect of acrolein-exacerbated MI was investigated. In vivo, male Sprague\u2013Dawley rats received olive leaf extract (OLE) followed by acrolein, then isoprenaline (ISO) was received by subcutaneous injection to induce MI. Results showed that the expression levels of GRP78 and CHOP, two major components of endoplasmic reticulum (ER) stress were higher in the combination of acrolein and ISO than those in ISO treatment. The apoptosis marker, Bax, was also higher while the anti-apoptosis indicator, Bcl2 expression was lower both at protein and mRNA levels in the combination group. Also, the acrolein-protein adducts and myocardial pathological damage increased in the combination of acrolein and ISO relative to the ISO treatment. Besides, cardiac parameters, ejection fraction (EF) and fractional shortening (FS) were reduced more significantly when acrolein was added than in ISO treatment. Interestingly, all the changes were able to be ameliorated by OLE. Since hydroxytyrosol (HT) and oleuropein (OP) were the main components in OLE, we next investigated the effect of HT and OP on cardiomyocyte H9c2 cell apoptosis induced by acrolein through ER stress and Bax pathway. Results showed that GRP78, CHOP and Bax expression were upregulated, while Bcl2 expression was downregulated both at the protein and mRNA levels, when the H9c2 cells were treated with acrolein. In addition, pretreatment with HT can reverse the expression of GRP78, CHOP, Bax and Bcl2 on the protein and mRNA levels, while there was no effect of OP on the expression of GRP78 and CHOP on the mRNA levels. Overall, all these results demonstrated that OLE and the main components (HT and OP) could prevent the negative effects of acrolein on myocardium and cardiomyocytes.<\/jats:p>","DOI":"10.3390\/ijms19020493","type":"journal-article","created":{"date-parts":[[2018,2,7]],"date-time":"2018-02-07T12:20:29Z","timestamp":1518006029000},"page":"493","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Protective Effects of Olive Leaf Extract on Acrolein-Exacerbated Myocardial Infarction via an Endoplasmic Reticulum Stress Pathway"],"prefix":"10.3390","volume":"19","author":[{"given":"Yuyu","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Hygiene, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, Nanjing Medical University, Nanjing 211166, China"},{"name":"Department of Cardiology, Jiangsu Province Hospital, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aochang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoqi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/S0140-6736(12)61728-0","article-title":"Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010","volume":"380","author":"Lozano","year":"2012","journal-title":"Lancet"},{"key":"ref_2","first-page":"e29","article-title":"Heart disease and stroke statistics--2015 update: A report from the American Heart Association","volume":"131","author":"Mozaffarian","year":"2015","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2810","DOI":"10.1161\/01.CIR.103.23.2810","article-title":"Increased particulate air pollution and the triggering of myocardial infarction","volume":"103","author":"Peters","year":"2001","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1093\/aje\/kwr046","article-title":"Short-term association between ambient air pollution and risk of hospitalization for acute myocardial infarction: Results of the cardiovascular risk and air pollution in Tuscany (RISCAT) study","volume":"174","author":"Nuvolone","year":"2011","journal-title":"Am. J. Epidemiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1289\/ehp.1001995","article-title":"Altered cardiac repolarization in association with air pollution and air temperature among myocardial infarction survivors","volume":"118","author":"Hampel","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1161\/CIR.0b013e3181dbece1","article-title":"Metabolism, Particulate matter air pollution and cardiovascular disease: An update to the scientific statement from the American Heart Association","volume":"121","author":"Brook","year":"2010","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1161\/CIRCULATIONAHA.106.636977","article-title":"Ischemic heart disease events triggered by short-term exposure to fine particulate air pollution","volume":"114","author":"Pope","year":"2006","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.talanta.2013.07.003","article-title":"Determination of carbonyl compounds in particulate matter PM2.5 by in-tube solid-phase microextraction coupled to capillary liquid chromatography\/mass spectrometry","volume":"115","year":"2013","journal-title":"Talanta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/mnfr.200700412","article-title":"Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease","volume":"52","author":"Stevens","year":"2008","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1002\/mnfr.201100481","article-title":"Toxicology and risk assessment of acrolein in food","volume":"55","author":"Abraham","year":"2011","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.atmosenv.2015.02.056","article-title":"Aldehydes in Relation to Air Pollution Sources: A Case Study around the Beijing Olympics","volume":"109","author":"Altemose","year":"2015","journal-title":"Atmos. Environ."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1002\/tox.20153","article-title":"Determination of toxic carbonyl compounds in cigarette smoke","volume":"21","author":"Fujioka","year":"2006","journal-title":"Environ. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15404","DOI":"10.1073\/pnas.0607031103","article-title":"Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair","volume":"103","author":"Feng","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1093\/toxsci\/kfu233","article-title":"Molecular Mechanisms of Acrolein Toxicity: Relevance to Human Disease","volume":"143","author":"Moghe","year":"2015","journal-title":"Toxicol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e000934","DOI":"10.1161\/JAHA.114.000934","article-title":"Acrolein exposure is associated with increased cardiovascular disease risk","volume":"3","author":"DeJarnett","year":"2014","journal-title":"J. Am. Heart Assoc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1093\/cvr\/cvq118","article-title":"Evidence for the pathophysiological relevance of TRPA1 receptors in the cardiovascular system in vivo","volume":"87","author":"Pozsgai","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.yjmcc.2008.03.020","article-title":"Acrolein consumption exacerbates myocardial ischemic injury and blocks nitric oxide-induced PKCepsilon signaling and cardioprotection","volume":"44","author":"Wang","year":"2008","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1111\/j.1753-4887.2009.00248.x","article-title":"Olive tree (Olea europaea) leaves: Potential beneficial effects on human health","volume":"67","author":"El","year":"2009","journal-title":"Nutr. Rev."},{"key":"ref_19","first-page":"571","article-title":"Diets for cardiovascular disease prevention: What is the evidence?","volume":"79","author":"Walker","year":"2009","journal-title":"Am. Fam. Physician"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.2174\/1389450117666161005150650","article-title":"Cardioprotective effects of the polyphenol hydroxytyrosol from olive oil","volume":"18","author":"Tejada","year":"2017","journal-title":"Curr. Drug Targets"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"946","DOI":"10.3945\/jn.109.117812","article-title":"Olive leaf extract attenuates cardiac, hepatic, and metabolic changes in high carbohydrate-, high fat-fed rats","volume":"140","author":"Poudyal","year":"2010","journal-title":"J. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s12012-014-9271-1","article-title":"Oleuropein offers cardioprotection in rats with acute myocardial infarction","volume":"15","author":"Janahmadi","year":"2015","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"538","DOI":"10.3109\/15376516.2015.1053648","article-title":"Preventive effects of oleuropein against cardiac remodeling after myocardial infarction in Wistar rat through inhibiting angiotensin-converting enzyme activity","volume":"25","author":"Mnafgui","year":"2015","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s12012-015-9323-1","article-title":"Protective Effect of Hydroxytyrosol Against Cardiac Remodeling After Isoproterenol-Induced Myocardial Infarction in Rat","volume":"16","author":"Mnafgui","year":"2016","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/nature17041","article-title":"Protein misfolding in the endoplasmic reticulum as a conduit to human disease","volume":"529","author":"Wang","year":"2016","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1146\/annurev-pathol-012513-104649","article-title":"The role of endoplasmic reticulum stress in human pathology","volume":"10","author":"Oakes","year":"2015","journal-title":"Ann. Rev. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1111\/jpi.12264","article-title":"Melatonin and endoplasmic reticulum stress: Relation to autophagy and apoptosis","volume":"59","author":"Fernandez","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1289\/ehp.8674","article-title":"The Effects of Air Pollution on Hospitalizations for Cardiovascular Disease in Elderly People in Australian and New Zealand Cities","volume":"114","author":"Barnett","year":"2006","journal-title":"Environ. Health Perspect."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nature07203","article-title":"From endoplasmic-reticulum stress to the inflammatory response","volume":"454","author":"Zhang","year":"2008","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nrm2199","article-title":"Signal integration in the endoplasmic reticulum unfolded protein response","volume":"8","author":"Ron","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/ncb0311-184","article-title":"Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress","volume":"13","author":"Tabas","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/cdd.2016.138","article-title":"SIRT1 protects the heart from ER stress-induced cell death through eIF2alpha deacetylation","volume":"24","author":"Prola","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1089\/ars.2009.2501","article-title":"Oxidative folding: Cellular strategies for dealing with the resultant equimolar production of reactive oxygen species","volume":"11","author":"Shimizu","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1146\/annurev-physiol-030212-183707","article-title":"Coping with endoplasmic reticulum stress in the cardiovascular system","volume":"75","author":"Groenendyk","year":"2013","journal-title":"Ann. Rev. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1161\/01.RES.0000233317.70421.03","article-title":"Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes","volume":"99","author":"Thuerauf","year":"2006","journal-title":"Circ. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1161\/CIRCULATIONAHA.109.917914","article-title":"Ablation of C\/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload","volume":"122","author":"Fu","year":"2010","journal-title":"Circulation"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/nature05124","article-title":"AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP","volume":"443","author":"Paton","year":"2006","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"309","DOI":"10.3109\/10408448509037461","article-title":"A critical review of the literature on acrolein toxicity","volume":"14","author":"Beauchamp","year":"1985","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s12012-016-9396-5","article-title":"Acrolein Can Cause Cardiovascular Disease: A Review","volume":"17","author":"Henning","year":"2017","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"H3673","DOI":"10.1152\/ajpheart.00284.2007","article-title":"Mechanisms of acrolein-induced myocardial dysfunction: Implications for environmental and endogenous aldehyde exposure","volume":"293","author":"Luo","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1161\/CIRCRESAHA.114.305518","article-title":"Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury","volume":"117","author":"Conklin","year":"2015","journal-title":"Circ. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"981","DOI":"10.5650\/jos.62.981","article-title":"Effect of storage on refined olive oil composition: Stabilization by addition of chlorophyll pigments and squalene","volume":"62","author":"Rigane","year":"2013","journal-title":"J. Oleo Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1055\/s-0034-1382881","article-title":"Olive leaf extracts protect cardiomyocytes against 4-hydroxynonenal-induced toxicity in vitro: Comparison with oleuropein, hydroxytyrosol, and quercetin","volume":"80","author":"Bali","year":"2014","journal-title":"Planta Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.foodchem.2016.06.001","article-title":"Phenolic content and antioxidant activity of olive by-products and antioxidant film containing olive leaf extract","volume":"212","author":"Moudache","year":"2016","journal-title":"Food Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1111\/ggi.12192","article-title":"Olive leaf extract decreases age-induced oxidative stress in major organs of aged rats","volume":"14","author":"Coban","year":"2014","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1515\/acph-2016-0033","article-title":"Olive leaf extract activity against Candida albicans and C. dubliniensis\u2014The in vitro viability study","volume":"66","author":"Zoric","year":"2016","journal-title":"Acta Pharm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.foodres.2016.12.017","article-title":"Evaluation of an olive leaf extract as a natural source of antiglycative compounds","volume":"92","author":"Navarro","year":"2017","journal-title":"Food Res. Int."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Boss, A., Bishop, K.S., Marlow, G., Barnett, M.P., and Ferguson, L.R. (2016). Evidence to Support the Anti-Cancer Effect of Olive Leaf Extract and Future Directions. Nutrients, 8.","DOI":"10.3390\/nu8080513"},{"key":"ref_50","first-page":"1137","article-title":"Protective effect of olive leaf extract on hippocampal injury induced by transient global cerebral ischemia and reperfusion in Mongolian gerbils","volume":"18","author":"Dekanski","year":"2011","journal-title":"Phytomed. Int. J. Phytother. Phytopharm."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Gentile, L., Uccella, N., and Sivakumar, G. (2017). Soft-MS and Computational Mapping of Oleuropein. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18050992"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.atherosclerosis.2013.07.005","article-title":"Regulation of antioxidant system, lipids and fatty acid beta-oxidation contributes to the cardioprotective effect of sodium tanshinone IIA sulphonate in isoproterenol-induced myocardial infarction in rats","volume":"230","author":"Wei","year":"2013","journal-title":"Atherosclerosis"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1002\/ptr.2688","article-title":"Cardioprotective potential of myricetin in isoproterenol-induced myocardial infarction in Wistar rats","volume":"23","author":"Tiwari","year":"2009","journal-title":"Phytother. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.lfs.2014.04.035","article-title":"Cardioprotective effect of embelin on isoproterenol-induced myocardial injury in rats: Possible involvement of mitochondrial dysfunction and apoptosis","volume":"107","author":"Sahu","year":"2014","journal-title":"Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1002\/ptr.4634","article-title":"Oleuropein, chief constituent of olive leaf extract, prevents the development of morphine antinociceptive tolerance through inhibition of morphine-induced L-type calcium channel overexpression","volume":"26","author":"Zare","year":"2012","journal-title":"Phytother. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.jep.2011.04.038","article-title":"Olive (Olea europaea L.) leaf extract attenuates early diabetic neuropathic pain through prevention of high glucose-induced apoptosis: In vitro and in vivo studies","volume":"136","author":"Kaeidi","year":"2011","journal-title":"J. Ethnopharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/493\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:54:04Z","timestamp":1760194444000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/493"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,7]]},"references-count":56,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,2]]}},"alternative-id":["ijms19020493"],"URL":"https:\/\/doi.org\/10.3390\/ijms19020493","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,7]]}}}