{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:46:32Z","timestamp":1790959592073,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T00:00:00Z","timestamp":1655078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"China Postdoctoral Science Foundation","award":["2021MD703903"],"award-info":[{"award-number":["2021MD703903"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Myocardial infarction (MI), a type of coronary heart disease, has had a significantly increased incidence in recent years. The balance of cardiomyocyte apoptosis and autophagy after MI is one of the main determinants of patient prognosis. Both affect myocardial fibrosis and ventricular remodeling and regulate cell survival. However, there are few studies on the regulation mechanism of cardiomyocyte autophagy and apoptosis in the early stage after MI. In this study, based on analyzing the scRNA-seq and mRNA-seq data of mice in the early stage of MI, we found that the expression of S100a8 and S100a9 increased first and then decreased in the early stage of MI, and their expression level changed with the number of neutrophils. Further, through the functional enrichment analysis of the differentially expressed genes, we found that S100a8 and S100a9 were simultaneously associated with autophagy and apoptosis and could regulate autophagy and apoptosis of cardiomyocytes through MAPK or PI3K-AKT signaling pathways. This study provides valuable insights for clarifying the pathogenesis of early stage MI and improving its early treatment.<\/jats:p>","DOI":"10.3390\/cells11121911","type":"journal-article","created":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T22:00:38Z","timestamp":1655157638000},"page":"1911","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Integrated Analysis Reveals S100a8\/a9 Regulates Autophagy and Apoptosis through the MAPK and PI3K-AKT Signaling Pathway in the Early Stage of Myocardial Infarction"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7476-2751","authenticated-orcid":false,"given":"Weijue","family":"Yi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongli","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7545-263X","authenticated-orcid":false,"given":"Xiuyang","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6688-1432","authenticated-orcid":false,"given":"Fengmin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1161\/CIRCULATIONAHA.109.873224","article-title":"Primary angioplasty versus fibrinolysis in acute myocardial infarction: Long-term follow-up in the Danish acute myocardial infarction 2 trial","volume":"121","author":"Nielsen","year":"2010","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1002\/cphy.c150006","article-title":"Pathophysiology of Myocardial Infarction","volume":"5","author":"Frangogiannis","year":"2015","journal-title":"Compr. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1016\/j.jacc.2016.01.069","article-title":"Relationship Between Infarct Size and Outcomes Following Primary PCI: Patient-Level Analysis From 10 Randomized Trials","volume":"67","author":"Stone","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41569-018-0036-6","article-title":"Therapeutic approaches for cardiac regeneration and repair","volume":"15","author":"Hashimoto","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e008024","DOI":"10.1161\/JAHA.117.008024","article-title":"Inflammation, Autophagy, and Apoptosis after Myocardial Infarction","volume":"7","author":"Wang","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/cr.2009.129","article-title":"S100A8\/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3","volume":"20","author":"Ghavami","year":"2010","journal-title":"Cell Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/nrcardio.2017.35","article-title":"Myocardial stress and autophagy: Mechanisms and potential therapies","volume":"14","author":"Delbridge","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1089\/ars.2017.7234","article-title":"Autophagy in Human Health and Disease: Novel Therapeutic Opportunities","volume":"30","author":"Giampieri","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1172\/JCI78652","article-title":"Autophagy: A druggable process that is deregulated in aging and human disease","volume":"125","author":"Kroemer","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5965","DOI":"10.1007\/s00253-018-9058-6","article-title":"Deacetylmycoepoxydiene is an agonist of Rac1, and simultaneously induces autophagy and apoptosis","volume":"102","author":"Xie","year":"2018","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_11","first-page":"195","article-title":"Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling","volume":"45","author":"Gao","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1016\/j.jacc.2018.02.066","article-title":"Trehalose-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction","volume":"71","author":"Sciarretta","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4886","DOI":"10.1111\/jcmm.13754","article-title":"Knockdown of lncRNA AK139328 alleviates myocardial ischaemia\/reperfusion injury in diabetic mice via modulating miR-204-3p and inhibiting autophagy","volume":"22","author":"Yu","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1161\/CIRCRESAHA.116.303356","article-title":"Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress","volume":"116","author":"Ikeda","year":"2015","journal-title":"Circ. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1007\/s10059-013-2269-x","article-title":"S100A8 and S100A9 promotes invasion and migration through p38 mitogen-activated protein kinase-dependent NF-kappaB activation in gastric cancer cells","volume":"35","author":"Kwon","year":"2013","journal-title":"Mol. Cells"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7149408","DOI":"10.1155\/2020\/7149408","article-title":"S100A9 Increases IL-6 and RANKL Expressions through MAPKs and STAT3 Signaling Pathways in Osteocyte-Like Cells","volume":"2020","author":"Takagi","year":"2020","journal-title":"BioMed Res. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13020-020-00410-1","article-title":"Anemoside B4 ameliorates TNBS-induced colitis through S100A9\/MAPK\/NF-kappaB signaling pathway","volume":"16","author":"Zhang","year":"2021","journal-title":"Chin. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e232","DOI":"10.1161\/CIRCRESAHA.120.317200","article-title":"Dynamics of Cardiac Neutrophil Diversity in Murine Myocardial Infarction","volume":"127","author":"Vafadarnejad","year":"2020","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.cell.2020.06.030","article-title":"Type V Collagen in Scar Tissue Regulates the Size of Scar after Heart Injury","volume":"182","author":"Yokota","year":"2020","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1016\/j.bcp.2006.05.017","article-title":"S100A8 and S100A9 in inflammation and cancer","volume":"72","author":"Gebhardt","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1161\/CIRCRESAHA.107.167544","article-title":"S100A8 and S100A9 mediate endotoxin-induced cardiomyocyte dysfunction via the receptor for advanced glycation end products","volume":"102","author":"Boyd","year":"2008","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1161\/ATVBAHA.121.317113","article-title":"Neutrophil-Derived Protein S100A8\/A9 Alters the Platelet Proteome in Acute Myocardial Infarction and Is Associated with Changes in Platelet Reactivity","volume":"42","author":"Joshi","year":"2022","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1161\/CIRCULATIONAHA.117.030742","article-title":"Single-Cell Sequencing of the Healthy and Diseased Heart Reveals Cytoskeleton-Associated Protein 4 as a New Modulator of Fibroblasts Activation","volume":"138","author":"Gladka","year":"2018","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1158\/0008-5472.CAN-17-2728","article-title":"Single-Cell Transcriptome Analyses Reveal Endothelial Cell Heterogeneity in Tumors and Changes following Antiangiogenic Treatment","volume":"78","author":"Zhao","year":"2018","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Yang, M., Zeng, P., Kang, R., Yu, Y., Yang, L., Tang, D., and Cao, L. (2014). S100A8 contributes to drug resistance by promoting autophagy in leukemia cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097242"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1111\/exd.12187","article-title":"TNFalpha- and IL-17A-mediated S100A8 expression is regulated by p38 MAPK","volume":"22","author":"Mose","year":"2013","journal-title":"Exp. Dermatol."},{"key":"ref_27","first-page":"2684","article-title":"IL-17 signaling pathway plays a key role in laryngeal squamous cell carcinoma with ethnic specificity","volume":"11","author":"Qi","year":"2021","journal-title":"Am. J. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.molimm.2015.05.014","article-title":"S100A9-induced release of interleukin (IL)-6 and IL-8 through toll-like receptor 4 (TLR4) in human periodontal ligament cells","volume":"67","author":"Gao","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1161\/CIRCULATIONAHA.118.039262","article-title":"S100a8\/a9 Signaling Causes Mitochondrial Dysfunction and Cardiomyocyte Death in Response to Ischemic\/Reperfusion Injury","volume":"140","author":"Li","year":"2019","journal-title":"Circulation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/S0968-0004(96)80167-8","article-title":"The S100 family of EF-hand calcium-binding proteins: Functions and pathology","volume":"21","author":"Schafer","year":"1996","journal-title":"Trends Biochem. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.cca.2019.11.019","article-title":"S100 proteins in atherosclerosis","volume":"502","author":"Xiao","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nrc3893","article-title":"S100 proteins in cancer","volume":"15","author":"Bresnick","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.3389\/fonc.2020.01101","article-title":"Identification and Validation of Stage-Associated PBMC Biomarkers in Breast Cancer Using MS-Based Proteomics","volume":"10","author":"Moradpoor","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s11010-016-2849-0","article-title":"Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research","volume":"424","author":"Rai","year":"2017","journal-title":"Mol. Cell. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1161\/CIRCRESAHA.111.243162","article-title":"Regulation of the inflammatory response in cardiac repair","volume":"110","author":"Frangogiannis","year":"2012","journal-title":"Circ. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s00018-013-1349-6","article-title":"The pathogenesis of cardiac fibrosis","volume":"71","author":"Kong","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s00395-019-0722-5","article-title":"Inflammation and fibrosis in murine models of heart failure","volume":"114","author":"Bacmeister","year":"2019","journal-title":"Basic Res. Cardiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1076029620943295","DOI":"10.1177\/1076029620943295","article-title":"The Association Between S100A8\/A9 and the Development of Very Late Stent Thrombosis in Patients with Acute Myocardial Infarction","volume":"26","author":"Wang","year":"2020","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1002\/ehf2.12760","article-title":"Serum alarmin S100A8\/S100A9 levels and its potential role as biomarker in myocarditis","volume":"7","author":"Muller","year":"2020","journal-title":"ESC Heart Fail."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"105212","DOI":"10.1016\/j.phrs.2020.105212","article-title":"Emerging roles of neutrophil-borne S100A8\/A9 in cardiovascular inflammation","volume":"161","author":"Sreejit","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1136\/hrt.2007.121640","article-title":"Increased serum levels and expression of S100A8\/A9 complex in infiltrated neutrophils in atherosclerotic plaque of unstable angina","volume":"94","author":"Miyamoto","year":"2008","journal-title":"Heart"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.cell.2010.02.029","article-title":"Nonresolving inflammation","volume":"140","author":"Nathan","year":"2010","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1038\/emboj.2012.151","article-title":"Pex3-anchored Atg36 tags peroxisomes for degradation in Saccharomyces cerevisiae","volume":"31","author":"Motley","year":"2012","journal-title":"EMBO J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6861","DOI":"10.1158\/0008-5472.CAN-05-3557","article-title":"Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase\/extracellular signal-regulated kinase activity","volume":"66","author":"Corcelle","year":"2006","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.ebiom.2018.08.035","article-title":"Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-kappaB pathway quenches intestinal inflammation and oxidative stress injury","volume":"35","author":"Zhou","year":"2018","journal-title":"eBioMedicine"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00253-019-10257-8","article-title":"Targeting PI3K\/AKT\/mTOR-mediated autophagy for tumor therapy","volume":"104","author":"Xu","year":"2020","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e12739","DOI":"10.1111\/cpr.12739","article-title":"Tanshinone I attenuates the malignant biological properties of ovarian cancer by inducing apoptosis and autophagy via the inactivation of PI3K\/AKT\/mTOR pathway","volume":"53","author":"Zhou","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/s41419-019-2013-3","article-title":"Matrine inhibits the development and progression of ovarian cancer by repressing cancer associated phosphorylation signaling pathways","volume":"10","author":"Zhang","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s10123-019-00077-1","article-title":"Fungal homologues of human Rac1 as emerging players in signal transduction and morphogenesis","volume":"23","author":"Huhn","year":"2020","journal-title":"Int. Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Boteanu, R.M., Suica, V.I., Uyy, E., Ivan, L., Cerveanu-Hogas, A., Mares, R.G., Simionescu, M., Schiopu, A., and Antohe, F. (2022). Short-Term Blockade of Pro-Inflammatory Alarmin S100A9 Favorably Modulates Left Ventricle Proteome and Related Signaling Pathways Involved in Post-Myocardial Infarction Recovery. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095289"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1161\/CIRCRESAHA.120.315865","article-title":"S100A9 Links Inflammation and Repair in Myocardial Infarction","volume":"127","author":"Marinkovic","year":"2020","journal-title":"Circ. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1006\/jmcc.2002.2005","article-title":"Transcriptional activation of the BNP gene by lipopolysaccharide is mediated through GATA elements in neonatal rat cardiac myocytes","volume":"34","author":"Tomaru","year":"2002","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1093\/eurjhf\/hfp076","article-title":"Activated cell survival cascade protects cardiomyocytes from cell death in Tako-Tsubo cardiomyopathy","volume":"11","author":"Nef","year":"2009","journal-title":"Eur. J. Heart Fail."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/12\/1911\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:30:22Z","timestamp":1760139022000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/12\/1911"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,13]]},"references-count":53,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["cells11121911"],"URL":"https:\/\/doi.org\/10.3390\/cells11121911","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,13]]}}}