S100A4-shRNA mitigates autophagy, reduces inflammation, and improves cardiac functionality in MIRI

IF 2.1 Q3 PERIPHERAL VASCULAR DISEASE
Guangwei Huang , Qing Huang , Chenrui Mou , Anna Duan , Fujiao He , Hailong Dai
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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.
S100A4-shRNA在MIRI中减轻自噬,减少炎症,改善心脏功能
ds100a4在心肌缺血-再灌注损伤(MIRI)中起着至关重要的作用,自噬和炎症之间的相互作用决定了再灌注损伤的进展。然而,在这种情况下,S100A4影响自噬和炎症的具体机制尚不清楚。方法建立小鼠缺血再灌注(I/R)模型。确定诱导再灌注损伤的最佳时机,将小鼠分为假手术组和实验组。实验组大鼠缺血再灌注2 h,再灌注2 d。在I/R + S100A4-shRNA组中,通过注射短发夹RNA (short hairpin RNA, shRNA)实现S100A4的沉默。阻断冠状动脉左前降支引起心肌缺血。诊断程序包括心电图评估、心功能测试、心酶分析和2,3,5-三苯基四氯化氮(TTC)染色来评估心肌损伤。采用免疫组织化学、免疫荧光染色、苏木精-伊红(HE)染色、Masson三色染色评价IL-1、TNF-a表达水平、心肌细胞形态学变化及心肌纤维化情况。蛋白印迹检测自噬相关蛋白和Bnip3信号相关蛋白。结果S100A4表达增加,自噬调控蛋白Beclin-1和LC3表达上调,导致心肌损伤和心肌梗死(MI)扩大。S100A4在MIRI中通过BNIP3途径调控自噬,发挥了多方面的作用。沉默S100A4导致自噬和炎症减少,导致梗死面积减小和心功能改善。结论ss100a4在MIRI过程中表达上调,并通过BNIP3途径调控自噬,影响心肌梗死后再灌注损伤的进展。S100A4-shRNA对自噬的抑制和炎症反应的缓解提供了对IRI对心脏有害影响的保护。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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