Guangwei Huang , Qing Huang , Chenrui Mou , Anna Duan , Fujiao He , Hailong Dai
{"title":"S100A4-shRNA mitigates autophagy, reduces inflammation, and improves cardiac functionality in MIRI","authors":"Guangwei Huang , Qing Huang , Chenrui Mou , Anna Duan , Fujiao He , Hailong Dai","doi":"10.1016/j.ijcrp.2025.200443","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>S100A4 plays a crucial role in myocardial ischemia-reperfusion injury (MIRI), where the interplay between autophagy and inflammation shapes the progression of reperfusion injury. However, the specific mechanisms by which S100A4 influences autophagy and inflammation in this context remain unclear.</div></div><div><h3>Methods</h3><div>An ischemia-reperfusion (I/R) model was established in mice. The optimal timing for inducing reperfusion injury was determined, and mice were divided into sham and experimental groups. The experimental group underwent 2 h of ischemia/reperfusion injury followed by a 2-day reperfusion period. In the I/R + S100A4-shRNA group, S100A4 silencing was achieved through the injection of short hairpin RNA (shRNA). Myocardial ischemia was induced by occluding the left anterior descending branch (LAD) of the coronary artery. Diagnostic procedures, including electrocardiogram assessments, cardiac function testing, cardiac enzyme analyses, and 2,3,5-triphenyl tetrazolium chloride (TTC) staining, were performed to assess myocardial injury. Immunohistochemistry, immunofluorescence staining, hematoxylin-eosin (HE) staining, and Masson trichrome staining were used to evaluate the expression levels of IL-1, TNF-a, morphological changes in cardiomyocytes, and cardiac fibrosis. Protein blotting was conducted to examine autophagy-related proteins and Bnip3 signaling-related proteins.</div></div><div><h3>Results</h3><div>The study showed an increase in S100A4 expression, as well as upregulation of autophagy orchestrating proteins (Beclin-1 and LC3), contributing to myocardial injury and expansion of myocardial infarction (MI). S100A4 played a multifaceted role by regulating autophagy through the BNIP3 pathway in MIRI. Silencing S100A4 resulted in reduced autophagy and inflammation, leading to decreased infarct size and improved cardiac function.</div></div><div><h3>Conclusions</h3><div>S100A4 is upregulated during MIRI and orchestrates autophagy through the BNIP3 pathway, influencing the progression of reperfusion injury following myocardial infarction. Inhibition of autophagy and mitigation of inflammatory responses by S100A4-shRNA provide protection against the detrimental effects of IRI on the heart.</div></div>","PeriodicalId":29726,"journal":{"name":"International Journal of Cardiology Cardiovascular Risk and Prevention","volume":"26 ","pages":"Article 200443"},"PeriodicalIF":2.1000,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Cardiology Cardiovascular Risk and Prevention","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2772487525000819","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
引用次数: 0
Abstract
Background
S100A4 plays a crucial role in myocardial ischemia-reperfusion injury (MIRI), where the interplay between autophagy and inflammation shapes the progression of reperfusion injury. However, the specific mechanisms by which S100A4 influences autophagy and inflammation in this context remain unclear.
Methods
An ischemia-reperfusion (I/R) model was established in mice. The optimal timing for inducing reperfusion injury was determined, and mice were divided into sham and experimental groups. The experimental group underwent 2 h of ischemia/reperfusion injury followed by a 2-day reperfusion period. In the I/R + S100A4-shRNA group, S100A4 silencing was achieved through the injection of short hairpin RNA (shRNA). Myocardial ischemia was induced by occluding the left anterior descending branch (LAD) of the coronary artery. Diagnostic procedures, including electrocardiogram assessments, cardiac function testing, cardiac enzyme analyses, and 2,3,5-triphenyl tetrazolium chloride (TTC) staining, were performed to assess myocardial injury. Immunohistochemistry, immunofluorescence staining, hematoxylin-eosin (HE) staining, and Masson trichrome staining were used to evaluate the expression levels of IL-1, TNF-a, morphological changes in cardiomyocytes, and cardiac fibrosis. Protein blotting was conducted to examine autophagy-related proteins and Bnip3 signaling-related proteins.
Results
The study showed an increase in S100A4 expression, as well as upregulation of autophagy orchestrating proteins (Beclin-1 and LC3), contributing to myocardial injury and expansion of myocardial infarction (MI). S100A4 played a multifaceted role by regulating autophagy through the BNIP3 pathway in MIRI. Silencing S100A4 resulted in reduced autophagy and inflammation, leading to decreased infarct size and improved cardiac function.
Conclusions
S100A4 is upregulated during MIRI and orchestrates autophagy through the BNIP3 pathway, influencing the progression of reperfusion injury following myocardial infarction. Inhibition of autophagy and mitigation of inflammatory responses by S100A4-shRNA provide protection against the detrimental effects of IRI on the heart.