{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T22:31:59Z","timestamp":1782513119293,"version":"3.54.5"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T00:00:00Z","timestamp":1607040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770292"],"award-info":[{"award-number":["81770292"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Myocardial infarction is one of the most serious fatal diseases in the world, which is due to acute occlusion of coronary arteries. Grape seed proanthocyanidin extract (GSPE) is an active compound extracted from grape seeds that has anti-oxidative, anti-inflammatory and anti-tumor pharmacological effects. Natural products are cheap, easy to obtain, widely used and effective. It has been used to treat numerous diseases, such as cancer, brain injury and diabetes complications. However, there are limited studies on its role and associated mechanisms in myocardial infarction in mice. This study showed that GSPE treatment in mice significantly reduced cardiac dysfunction and improved the pathological changes due to MI injury.<jats:italic>In vitro<\/jats:italic>, GSPE inhibited the apoptosis of H9C2 cells after hypoxia culture, resulting in the expression of Bax decreased and the expression of Bcl-2 increased. The high expression of p-PI3K and p-AKT was detected in MI model<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>. The use of the specific PI3K\/AKT pathway inhibitor LY294002 regressed the cardio-protection of GSPE. Our results showed that GSPE could improve the cardiac dysfunction and remodeling induced by MI and inhibit cardiomyocytes apoptosis in hypoxic conditions through the PI3K\/AKT signaling pathway.<\/jats:p>","DOI":"10.3389\/fphar.2020.585984","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T16:09:14Z","timestamp":1607098154000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["Grape Seed Proanthocyanidin Extract Ameliorates Cardiac Remodelling After Myocardial Infarction Through PI3K\/AKT Pathway in Mice"],"prefix":"10.3389","volume":"11","author":[{"given":"Yongxue","family":"Ruan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qike","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangfang","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuoyi","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangting","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianpin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingguo","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"545","DOI":"10.3390\/antiox9060545","article-title":"Neuroprotection by phytoestrogens in the model of deprivation and resupply of oxygen and glucose in vitro: the contribution of autophagy and related signaling mechanisms","volume":"9","author":"Abbruzzese","year":"2020","journal-title":"Antioxidants"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1126\/science.281.5381.1322","article-title":"The Bcl-2 protein family: arbiters of cell survival","volume":"281","author":"Adams","year":"1998","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1007\/s00395-015-0526-1","article-title":"Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K\/Akt-dependent mechanism","volume":"111","author":"An","year":"2016","journal-title":"Basic Res. Cardiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1111\/bph.14549","article-title":"Exogenous IL-19 attenuates acute ischaemic injury and improves survival in male mice with myocardial infarction","volume":"176","author":"An","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.ejphar.2015.09.023","article-title":"Atorvastatin protects myocardium against ischemia-reperfusion arrhythmia by increasing Connexin 43 expression: a rat model","volume":"768","author":"Bian","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1002\/mnfr.200900476","article-title":"Hypolipidemic effects of proanthocyanidins and their underlying biochemical and molecular mechanisms","volume":"54","author":"Blad\u00e9","year":"2010","journal-title":"Mol. Nutr. Food Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/j.molcel.2019.12.025","article-title":"Allosteric regulation of BH3 proteins in bcl-x(L) complexes enables switch-like activation of Bax","volume":"77","author":"Bogner","year":"2020","journal-title":"Mol. Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1007\/s00395-010-0133-0","article-title":"Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K\/Akt-dependent cell-survival signaling at reperfusion","volume":"106","author":"Breivik","year":"2011","journal-title":"Basic Res. Cardiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1007\/s00395-011-0199-3","article-title":"Burn-induced apoptosis of cardiomyocytes is survivin dependent and regulated by PI3K\/Akt, p38 MAPK and ERK pathways","volume":"106","author":"Cao","year":"2011","journal-title":"Basic Res. Cardiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1186\/s12974-020-01853-x","article-title":"TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K\/Akt pathway after intracerebral hemorrhage in mice","volume":"17","author":"Chen","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"B11","doi-asserted-by":"publisher","first-page":"4451","DOI":"10.1172\/jci126091","article-title":"Identifying and targeting pathogenic PI3K\/AKT\/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease","volume":"129","author":"Fajgenbaum","year":"2019","journal-title":"J. Clin. Invest."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.3892\/mmr.2018.9140","article-title":"Grape seed proanthocyanidins protect against streptozotocin-induced diabetic nephropathy by attenuating endoplasmic reticulum stress-induced apoptosis","volume":"18","author":"Gao","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"116","DOI":"10.3736\/jintegrmed2013014","article-title":"Homeopathic mother tincture of Phytolacca decandra induces apoptosis in skin melanoma cells by activating caspase-mediated signaling via reactive oxygen species elevation","volume":"11","author":"Ghosh","year":"2013","journal-title":"J. Integr. med."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s00394-020-02222-3","article-title":"Protective properties of grape-seed proanthocyanidins in human ex vivo acute colonic dysfunction induced by dextran sodium sulfate","author":"Gonz\u00e1lez-Quilen","year":"2020","journal-title":"Eur. J. Nutr."},{"key":"B15","doi-asserted-by":"publisher","first-page":"39","DOI":"10.2174\/0929867321666140916115519","article-title":"Procyanidins and their healthy protective effects against type 2 diabetes","volume":"22","author":"Gonzalez-Abuin","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"3403972","DOI":"10.1155\/2018\/3403972","article-title":"Grape seed proanthocyanidin extract inhibits human esophageal squamous cancerous cell line ECA109 via the NF-\u03baB signaling pathway","volume":"2018","author":"Guo","year":"2018","journal-title":"Mediators Inflamm."},{"key":"B17","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1161\/res.35.3_supplement.iii-156","article-title":"Structural changes in myocardium during acute ischemia","volume":"35","author":"Jennings","year":"1974","journal-title":"Circ. Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1016\/j.jcmg.2011.06.004","article-title":"Can a teaching intervention reduce interobserver variability in LVEF assessment: a quality control exercise in the echocardiography lab","volume":"4","author":"Johri","year":"2011","journal-title":"JACC Cardiovascular imaging"},{"key":"B19","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s12964-014-0071-9","article-title":"Nck1 depletion induces activation of the PI3K\/Akt pathway by attenuating PTP1B protein expression","volume":"12","author":"Li","year":"2014","journal-title":"Cell Commun. Signal."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2053149","DOI":"10.1155\/2019\/2053149","article-title":"CGRP reduces apoptosis of DRG cells induced by high-glucose oxidative stress injury through PI3K\/AKT induction of heme oxygenase-1 and nrf-2 expression","volume":"2019","author":"Liu","year":"2019","journal-title":"Oxid. Med. Cell. Longevity"},{"key":"B21","doi-asserted-by":"publisher","first-page":"148798","DOI":"10.1155\/2014\/148798","article-title":"Atorvastatin represses the angiotensin 2-induced oxidative stress and inflammatory response in dendritic cells via the PI3K\/Akt\/Nrf 2 pathway","volume":"2014","author":"Ma","year":"2014","journal-title":"Oxid. Med. Cell. Longev."},{"key":"B22","doi-asserted-by":"publisher","first-page":"10535","DOI":"10.1002\/jcp.27717","article-title":"Annexin A3 gene silencing promotes myocardial cell repair through activation of the PI3K\/Akt signaling pathway in rats with acute myocardial infarction","volume":"234","author":"Meng","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1007\/s00395-006-0622-3","article-title":"Impairment of cardioprotective PI3K-Akt signaling by post-infarct ventricular remodeling is compensated by an ERK-mediated pathway","volume":"102","author":"Miki","year":"2007","journal-title":"Basic Res. Cardiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1006\/jmcc.2002.2006","article-title":"PI3 kinase and not p42\/p44 appears to be implicated in the protection conferred by ischemic preconditioning","volume":"34","author":"Mocanu","year":"2002","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e0132451","DOI":"10.1371\/journal.pone.0132451","article-title":"A New Therapeutic Modality for Acute Myocardial Infarction: nanoparticle-Mediated Delivery of Pitavastatin Induces Cardioprotection from Ischemia-Reperfusion Injury via Activation of PI3K\/Akt Pathway and Anti-Inflammation in a Rat Model","volume":"10","author":"Nagaoka","year":"2015","journal-title":"PLoS One"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2929","DOI":"10.1093\/eurheartj\/ehu378","article-title":"Cardiovascular disease in Europe 2014: epidemiological update","volume":"35","author":"Nichols","year":"2014","journal-title":"Eur. Heart J."},{"key":"B27","doi-asserted-by":"publisher","first-page":"10761","DOI":"10.1074\/jbc.275.15.10761","article-title":"Akt\/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein","volume":"275","author":"Pugazhenthi","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B28","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/s0140-6736(16)30677-8","article-title":"Acute myocardial infarction","volume":"389","author":"Reed","year":"2017","journal-title":"Lancet"},{"key":"B29","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1016\/j.freeradbiomed.2003.12.012","article-title":"Flavonoids and isoflavones: absorption, metabolism, and bioactivity","volume":"36","author":"Rice-Evans","year":"2004","journal-title":"Free Radic. Biol. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1007\/s11011-018-0320-5","article-title":"Grape seed proanthocyanidin extract and insulin prevents cognitive decline in type 1 diabetic rat by impacting Bcl-2 and Bax in the prefrontal cortex","volume":"34","author":"Sanna","year":"2019","journal-title":"Metab. Brain Dis."},{"key":"B31","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.amjmed.2015.12.009","article-title":"Prognostic impact of myocardial injury related to various cardiac and noncardiac conditions","volume":"129","author":"Sarkisian","year":"2016","journal-title":"Am. J. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e5","DOI":"10.1016\/j.amjmed.2015.11.006","article-title":"Clinical characteristics and outcomes of patients with myocardial infarction, myocardial injury, and nonelevated troponins","volume":"129","author":"Sarkisian","year":"2016","journal-title":"Am. J. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1016\/s0891-5849(01)00626-8","article-title":"Grape seed proanthocyanidin reduces cardiomyocyte apoptosis by inhibiting ischemia\/reperfusion-induced activation of JNK-1 and C-JUN","volume":"31","author":"Sato","year":"2001","journal-title":"Free Radic. Biol. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1006\/jmcc.1999.0961","article-title":"Cardioprotective effects of grape seed proanthocyanidin against ischemic reperfusion injury","volume":"31","author":"Sato","year":"1999","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s00395-020-0804-4","article-title":"Deletion of newly described pro-survival molecule Pellino-1 increases oxidative stress, downregulates cIAP2\/NF-\u03baB cell survival pathway, reduces angiogenic response, and thereby aggravates tissue function in mouse ischemic models","volume":"115","author":"Selvaraju","year":"2020","journal-title":"Basic Res. Cardiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1002\/jcb.22170","article-title":"Grape seed proanthocyanidins protect cardiomyocytes from ischemia and reperfusion injury via Akt-NOS signaling","volume":"107","author":"Shao","year":"2009","journal-title":"J. Cell. Biochem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s10565-006-0052-x","article-title":"Cytotoxicity induced by grape seed proanthocyanidins: role of nitric oxide","volume":"22","author":"Shao","year":"2006","journal-title":"Cell Biol. Toxicol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"5063","DOI":"10.1111\/jcmm.14367","article-title":"Sulodexide attenuates endoplasmic reticulum stress induced by myocardial ischaemia\/reperfusion by activating the PI3K\/Akt pathway","volume":"23","author":"Shen","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1016\/j.biopha.2017.07.039","article-title":"Immunohistochemical and biochemical alterations following administration of proanthocyanidin extract in rats hepatocellular carcinoma","volume":"93","author":"Sherif","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1002\/ptr.6318","article-title":"miR-96 and autophagy are involved in the beneficial effect of grape seed proanthocyanidins against high-fat-diet-induced dyslipidemia in mice","volume":"33","author":"Shi","year":"2019","journal-title":"Phytother Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1007\/s10495-009-0398-7","article-title":"Activation of Akt\/GSK-3beta signaling pathway is involved in intermedin(1-53) protection against myocardial apoptosis induced by ischemia\/reperfusion","volume":"14","author":"Song","year":"2009","journal-title":"Apoptosis"},{"key":"B42","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.gheart.2018.08.004","article-title":"Fourth universal definition of myocardial infarction (2018)","volume":"13","author":"Thygesen","year":"2018","journal-title":"Global heart"},{"key":"B43","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1007\/s10571-019-00691-7","article-title":"Pretreatment of grape seed proanthocyanidin extract exerts neuroprotective effect in murine model of neonatal hypoxic-ischemic brain injury by its antiapoptotic property","volume":"39","author":"Tu","year":"2019","journal-title":"Cell. Mol. Neurobiol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e2088","DOI":"10.1038\/cddis.2015.274","article-title":"c-Met and CREB1 are involved in miR-433-mediated inhibition of the epithelial-mesenchymal transition in bladder cancer by regulating Akt\/GSK-3\u03b2\/Snail signaling","volume":"7","author":"Xu","year":"2016","journal-title":"Cell Death Dis."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2155","DOI":"10.1056\/NEJMoa0908610","article-title":"Population trends in the incidence and outcomes of acute myocardial infarction","volume":"362","author":"Yeh","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"127341","DOI":"10.1016\/j.chemosphere.2020.127341","article-title":"Cadmium-induced oxidative stress promotes apoptosis and necrosis through the regulation of the miR-216a-PI3K\/AKT axis in common carp lymphocytes and antagonized by selenium","volume":"258","author":"Zhang","year":"2020","journal-title":"Chemosphere"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2020.585984\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T11:46:55Z","timestamp":1669981615000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2020.585984\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,4]]},"references-count":46,"alternative-id":["10.3389\/fphar.2020.585984"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2020.585984","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,4]]},"article-number":"585984"}}