Characterization of ferroptosis-triggered pyroptotic signaling in heart failure

IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Signal Transduction and Targeted Therapy Pub Date : 2024-09-25 DOI:10.1038/s41392-024-01962-6
Xukun Bi, Xiaotian Wu, Jiaqi Chen, Xiaoting Li, Yangjun Lin, Yingying Yu, Xuexian Fang, Xihao Cheng, Zhaoxian Cai, Tingting Jin, Shuxian Han, Meihui Wang, Peidong Han, Junxia Min, Guosheng Fu, Fudi Wang
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Abstract

Pressure overload–induced cardiac hypertrophy is a common cause of heart failure (HF), and emerging evidence suggests that excessive oxidized lipids have a detrimental effect on cardiomyocytes. However, the key regulator of lipid toxicity in cardiomyocytes during this pathological process remains unknown. Here, we used lipidomics profiling and RNA-seq analysis and found that phosphatidylethanolamines (PEs) and Acsl4 expression are significantly increased in mice with transverse aortic constriction (TAC)–induced HF compared to sham-operated mice. In addition, we found that overexpressing Acsl4 in cardiomyocytes exacerbates pressure overload‒induced cardiac dysfunction via ferroptosis. Notably, both pharmacological inhibition and genetic deletion of Acsl4 significantly reduced left ventricular chamber size and improved cardiac function in mice with TAC-induced HF. Moreover, silencing Acsl4 expression in cultured neonatal rat ventricular myocytes was sufficient to inhibit hypertrophic stimulus‒induced cell growth. Mechanistically, we found that Acsl4-dependent ferroptosis activates the pyroptotic signaling pathway, which leads to increased production of the proinflammatory cytokine IL-1β, and neutralizing IL-1β improved cardiac function in Acsl4 transgenic mice following TAC. These results indicate that ACSL4 plays an essential role in the heart during pressure overload‒induced cardiac remodeling via ferroptosis-induced pyroptotic signaling. Together, these findings provide compelling evidence that targeting the ACSL4-ferroptosis-pyroptotic signaling cascade may provide a promising therapeutic strategy for preventing heart failure.

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心力衰竭中铁蛋白沉积触发的热蛋白沉积信号的特征
压力过载引起的心脏肥大是心力衰竭(HF)的常见原因,新的证据表明,过多的氧化脂质对心肌细胞具有有害影响。然而,在这一病理过程中,心肌细胞中脂质毒性的关键调节因子仍然未知。在这里,我们利用脂质组学分析和 RNA-seq 分析发现,与假手术小鼠相比,横纹主动脉缩窄(TAC)诱导的高频小鼠体内磷脂酰乙醇胺(PEs)和 Acsl4 的表达显著增加。此外,我们还发现,在心肌细胞中过表达 Acsl4 会通过铁蛋白沉积加剧压力过载诱导的心功能不全。值得注意的是,药理抑制和基因敲除 Acsl4 都能显著缩小 TAC 诱导的高房颤动小鼠的左心室腔大小并改善其心脏功能。此外,在培养的新生大鼠心室肌细胞中沉默 Acsl4 的表达足以抑制肥大刺激诱导的细胞生长。从机理上讲,我们发现依赖于 Acsl4 的铁凋亡激活了热凋亡信号通路,导致促炎细胞因子 IL-1β 的产生增加,中和 IL-1β 可改善 Acsl4 转基因小鼠在 TAC 后的心功能。这些结果表明,在压力过载诱导的心脏重塑过程中,ACSL4 通过铁蛋白沉积诱导的热蛋白沉积信号在心脏中发挥着重要作用。总之,这些研究结果提供了令人信服的证据,表明针对 ACSL4-铁变态反应-热变态反应信号级联可为预防心力衰竭提供一种有前景的治疗策略。
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来源期刊
Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
44.50
自引率
1.50%
发文量
384
审稿时长
5 weeks
期刊介绍: Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
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