PDF(Pubmed)
Abstract：
The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune and inflammatory cells, potentially driven by abnormalities in their number and function due to diabetes, may play a significant role. In the present investigation, we simulated myocardial I/R injury by inducing ischemia through ligation of the left anterior descending coronary artery in mice for 40 min, followed by reperfusion for 24 h. Previous studies have indicated that protein kinase Cβ (PKCβ) is upregulated under hyperglycemic conditions and is implicated in the development of various diabetic complications. The Y4 RNA fragment is identified as the predominant small RNA component present in the extracellular vesicles of cardio sphere-derived cells (CDCs), exhibiting notable anti-inflammatory properties in the contexts of myocardial infarction and cardiac hypertrophy. Our investigation revealed that the administration of Y4 RNA into the ventricular cavity of db/db mice following myocardial I/R injury markedly enhanced cardiac function. Furthermore, Y4 RNA was observed to facilitate M2 macrophage polarization and interleukin-10 secretion through the suppression of PKCβ activation. The mechanism by which Y4 RNA affects PKCβ by regulating macrophage activation within the inflammatory environment involves the inhibition of ERK1/2 phosphorylation In our study, the role of PKCβ in regulating macrophage polarization during myocardial I/R injury was investigated through the use of PKCβ knockout mice. Our findings indicate that PKCβ plays a crucial role in modulating the inflammatory response associated with macrophage activation in db/db mice experiencing myocardial I/R, with a notable exacerbation of this response observed upon significant upregulation of PKCβ expression. In vitro studies further elucidated the protective mechanism by which Y4 RNA modulates the PKCβ/ERK1/2 signaling pathway to induce M2 macrophage activation. Overall, our findings suggest that Y4 RNA plays an anti-inflammatory role in diabetic I/R injury, suggesting a novel therapeutic approach for managing myocardial I/R injury in diabetic individuals.
摘要：
糖尿病加重心肌缺血/再灌注(I/R)损伤的具体病理生理途径尚不清楚;免疫和炎症细胞失调，可能是由于糖尿病引起的数量和功能异常，可以发挥重要作用。在目前的调查中,通过结扎小鼠冠状动脉左前降支40min诱导缺血模拟心肌I/R损伤,先前的研究表明，蛋白激酶Cβ（PKCβ）在高血糖条件下上调，并与各种糖尿病并发症的发展有关。Y4RNA片段被鉴定为存在于心球衍生细胞（CDCs）的胞外囊泡中的主要小RNA成分。在心肌梗死和心脏肥大的情况下表现出显著的抗炎特性。我们的研究表明，在心肌I/R损伤后，向db/db小鼠的心室腔内施用Y4RNA可显着增强心功能。此外，观察到Y4RNA通过抑制PKCβ活化促进M2巨噬细胞极化和白细胞介素-10分泌。Y4RNA通过调节炎症环境中的巨噬细胞活化影响PKCβ的机制涉及ERK1/2磷酸化的抑制。通过使用PKCβ敲除小鼠研究了PKCβ在调节心肌I/R损伤中巨噬细胞极化中的作用。我们的发现表明PKCβ在调节db/db小鼠心肌I/R中与巨噬细胞活化相关的炎症反应中起着至关重要的作用。在PKCβ表达显著上调后观察到该反应显著恶化。体外研究进一步阐明了Y4RNA调节PKCβ/ERK1/2信号通路以诱导M2巨噬细胞活化的保护机制。总的来说,我们的研究结果表明，Y4RNA在糖尿病I/R损伤中起抗炎作用，提示一种新的治疗糖尿病患者心肌I/R损伤的方法。
