雜志名稱：International Journal of Biological Sciences
影響因子：8.2
文章題目：microRNA-130b-3p Attenuates Septic Cardiomyopathy by Regulating the AMPK/mTOR Signaling Pathways and Directly Targeting ACSL4 against Ferroptosis
DOI: 10.7150/ijbs.82287
第一作者：Zhen Qi , Ruhui Liu , Haining Ju , Mengxi Huang , Zhe Li , Wei Li , Yongyi Wang
作者單位：
上海交通大學醫(yī)學院附屬仁濟醫(yī)院
四川大學華西第二大學醫(yī)院
上海中醫(yī)藥大學第七人民醫(yī)院
南京鼓樓醫(yī)院
引用YOBIBIO產(chǎn)品：
U96-5422E Mouse cTnI ELISA Kit
U96-5379E Mouse CK-MB ELISA Kit
文章摘要：
Ferroptosis is a newly identified type of programmed cell death that has been shown to contribute to the progression of septic cardiomyopathy. Although the role of miR-130b-3p as an oncogene that accelerates cancer progression by suppressing ferroptosis has been demonstrated, its role in the regulation of ferroptosis and cardiac injury in Lipopolysaccharide (LPS)-induced cardiomyopathy has not been fully clarified. In this study, we demonstrated that miR-130b-3p remarkably improved cardiac function and ameliorated morphological damage to heart tissue in LPS-induced mice. miR-130b-3p also improved cell viability and mitochondrial function and reduced the production of lipid ROS and ferroptosis in LPS-treated H9c2 cells. In addition, miR-130b-3p significantly upregulated GPX4 expression and suppressed ACSL4 activity in LPS-induced mouse heart tissue and H9c2 cells. Mechanistically, we used database analysis to locate miR-130b-3p and confirmed its inhibitory effects on the ferroptosis-related gene ACSL4 and autophagy-related gene PRKAA1 using a dual-luciferase reporter assay. In addition, we found that miR-130b-3p inhibited the activation of autophagy by downregulating the expression of the AMPK/mTOR signaling pathway. Meanwhile, our results show that RAPA (an autophagy activator) reverses the protective effect of miR-130b-3p mimic against LPS-induced ferroptosis, while CQ (an autophagy inhibitor) plays a facilitative role, suggesting that miR-130b-3p plays an important role in the development of ferroptosis by regulating autophagy in vitro. The findings reveal a novel function of miR-130b-3p in attenuating ferroptosis in cardiomyocytes, providing a new therapeutic target for ameliorating septic cardiomyopathy injury.
鐵死亡是一種新發(fā)現(xiàn)的程序性細胞死亡類型，已被證明有助于膿毒癥心肌病的進展。盡管miR-130b-3p作為癌基因通過抑制鐵死亡加速癌癥進展的作用已被證明，但其在脂多糖（LPS）誘導的心肌病中鐵死亡和心臟損傷的調節(jié)中的作用尚未完全闡明。在這項研究中，我們證明 miR-130b-3p 顯著改善了 LPS 誘導的小鼠的心臟功能并改善了心臟組織的形態(tài)損傷。miR-130b-3p 還可以改善 LPS 處理的 H9c2 細胞中的細胞活力和線粒體功能，并減少脂質 ROS 的產(chǎn)生和鐵死亡。此外，在LPS誘導的小鼠心臟組織和H9c2細胞中，miR-130b-3p顯著上調GPX4表達并抑制ACSL4活性。從機制上講，我們使用數(shù)據(jù)庫分析來定位 miR-130b-3p，并使用雙熒光素酶報告基因測定證實其對鐵死亡相關基因 ACSL4 和自噬相關基因 PRKAA1 的抑制作用。此外，我們發(fā)現(xiàn)miR-130b-3p通過下調AMPK/mTOR信號通路的表達來抑制自噬的激活。同時，我們的結果表明，RAPA（一種自噬激活劑）逆轉了 miR-130b-3p 模擬物對 LPS 誘導的鐵死亡的保護作用，而 CQ（一種自噬抑制劑）則起促進作用，這表明 miR-130b-3p 發(fā)揮著促進作用。通過體外調節(jié)自噬在鐵死亡的發(fā)展中發(fā)揮重要作用。研究結果揭示了 miR-130b-3p 在減輕心肌細胞鐵死亡方面的新功能，為改善膿毒癥心肌病損傷提供了新的治療靶點。
