CircSSR1 regulates pyroptosis of pulmonary artery smooth muscle cells through parental protein SSR1 mediating endoplasmic reticulum stress.

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-10-01 DOI:10.1186/s12931-024-02986-w
Xiaoyu Guan, Hongxia Du, Xiaoying Wang, Xiangrui Zhu, Cui Ma, Lixin Zhang, Siyu He, June Bai, Huiyu Liu, Hao Yuan, Shanshan Wang, Kuiyu Wan, Hang Yu, Daling Zhu
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Abstract

Introduction: Pyroptosis, inflammatory necrosis of cells, is a programmed cell death involved in the pathological process of diseases. Endoplasmic reticulum stress (ERS), as a protective stress response of cell, decreases the unfold protein concentration to inhibit the unfold protein agglutination. Whereas the relationship between endoplasmic reticulum stress and pyroptosis in pulmonary hypertension (PH) remain unknown. Previous evident indicated that circular RNA (circRNA) can participate in several biological process, including cell pyroptosis. However, the mechanism of circRNA regulate pyroptosis of pulmonary artery smooth muscle cells through endoplasmic reticulum stress still unclear. Here, we proved that circSSR1 was down-regulate expression during hypoxia in pulmonary artery smooth muscle cells, and over-expression of circSSR1 inhibit pyroptosis both in vitro and in vivo under hypoxic. Our experiments have indicated that circSSR1 could promote host gene SSR1 translation via m6A to activate ERS leading to pulmonary artery smooth muscle cell pyroptosis. In addition, our results showed that G3BP1 as upstream regulator mediate the expression of circSSR1 under hypoxia. These results highlight a new regulatory mechanism for pyroptosis and provide a potential therapy target for pulmonary hypertension.

Methods: RNA-FISH and qRT-PCR were showed the location of circSSR1 and expression change. RNA pull-down and RIP verify the circSSR1 combine with YTHDF1. Western blotting, PI staining and LDH release were used to explore the role of circSSR1 in PASMCs pyroptosis.

Results: CircSSR1 was markedly downregulated in hypoxic PASMCs. Knockdown CircSSR1 inhibited hypoxia induced PASMCs pyroptosis in vivo and in vitro. Mechanistically, circSSR1 combine with YTHDF1 to promote SSR1 protein translation rely on m6A, activating pyroptosis via endoplasmic reticulum stress. Furthermore, G3BP1 induce circSSR1 degradation under hypoxic.

Conclusion: Our findings clarify the role of circSSR1 up-regulated parental protein SSR1 expression mediate endoplasmic reticulum stress leading to pyroptosis in PASMCs, ultimately promoting the development of pulmonary hypertension.

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CircSSR1通过亲代蛋白SSR1介导内质网应激,调节肺动脉平滑肌细胞的热凋亡。
简介细胞凋亡(Pyroptosis),即细胞的炎性坏死,是一种程序性细胞死亡,参与疾病的病理过程。内质网应激(ERS)作为细胞的一种保护性应激反应,可降低未折叠蛋白浓度,抑制未折叠蛋白凝集。而肺动脉高压(PH)中内质网应激与热蛋白沉积之间的关系尚不清楚。以往的研究表明,环状核糖核酸(circRNA)可参与多个生物过程,包括细胞的热解。然而,circRNA通过内质网应激调控肺动脉平滑肌细胞热凋亡的机制仍不清楚。在这里,我们证实了circSSR1在缺氧时会在肺动脉平滑肌细胞中下调表达,而在体外和体内缺氧条件下,circSSR1的过度表达都会抑制细胞的析热。我们的实验表明,circSSR1可通过m6A促进宿主基因SSR1的翻译,从而激活ERS,导致肺动脉平滑肌细胞发生热休克。此外,我们的研究结果表明,G3BP1作为上游调控因子在缺氧条件下介导了circSSR1的表达。这些结果凸显了一种新的热凋亡调控机制,并为肺动脉高压提供了一个潜在的治疗靶点:RNA-FISH和qRT-PCR显示了circSSR1的位置和表达变化。RNA pull-down 和 RIP 验证了 circSSR1 与 YTHDF1 的结合。用 Western 印迹、PI 染色和 LDH 释放来探讨 circSSR1 在 PASMCs 热休克中的作用:结果:CircSSR1在缺氧的PASMCs中明显下调。结果:CircSSR1在缺氧的PASMCs中明显下调,敲除CircSSR1可抑制体内和体外缺氧诱导的PASMCs热凋亡。从机制上看,circSSR1与YTHDF1结合,依靠m6A促进SSR1蛋白翻译,通过内质网应激激活热凋亡。此外,在缺氧条件下,G3BP1诱导circSSR1降解:我们的研究结果阐明了circSSR1上调亲代蛋白SSR1表达介导内质网应激导致PASMCs热凋亡,最终促进肺动脉高压发展的作用。
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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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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