Klebsiella pneumoniae-derived extracellular vesicles impair endothelial function by inhibiting SIRT1.

IF 8.2 2区生物学 Q1 CELL BIOLOGY Cell Communication and Signaling Pub Date : 2025-01-13 DOI:10.1186/s12964-024-02002-0

Xinxin Li, Jinghua Cui, Zanbo Ding, Ziyan Tian, Yiming Kong, Linghai Li, Yang Liu, Wen Zhao, Xueying Chen, Han Guo, Zhengshuo Cui, Xinwei Li, Jing Yuan, Huina Zhang

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Abstract

Background: The potential role of Klebsiella pneumoniae (K.pn) in hypertension development has been emphasized, although the specific mechanisms have not been well understood. Bacterial extracellular vesicles (BEVs) released by Gram-negative bacteria modulate host cell functions by delivering bacterial components to host cells. Endothelial dysfunction is an important early event in the pathogenesis of hypertension, yet the impact of K.pn-secreted EVs (K.pn EVs) on endothelial function remains unclear. This study aimed to investigate the effects of K.pn EVs on endothelial function and to elucidate the underlying mechanisms.

Methods: K.pn EVs were purified from the bacterial suspension using ultracentrifugation and characterized by transmission electron microscopy nanoparticle tracking analysis, and EV marker expression. Endothelium-dependent relaxation was measured using a wire myograph after in vivo or ex vivo treatment with K.pn EVs. Superoxide anion production was measured by confocal microscopy and HUVEC senescence was assessed by SA-β-gal activity. SIRT1 overexpression or activator was utilized to investigate the underlying mechanisms.

Results: Our data showed that K.pn significantly impaired acetylcholine-induced endothelium-dependent relaxation and increased superoxide anion production in endothelial cells in vivo. Similarly, in vivo and ex vivo studies showed that K.pn EVs caused significant endothelial dysfunction, endothelial provocation, and increased blood pressure. Further examination revealed that K.pn EVs reduced the levels of SIRT1 and p-eNOS and increased the levels of NOX2, COX-2, ET-1, and p53 in endothelial cells. Notably, overexpression or activation of SIRT1 attenuated the adverse effects and protein changes induced by K.pn EVs on endothelial cells.

Conclusion: This study reveals a novel role of K.pn EVs in endothelial dysfunction and dissects the relevant mechanism involved in this process, which will help to establish a comprehensive understanding of K.pn EVs in endothelial dysfunction and hypertension from a new scope.

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肺炎克雷伯菌衍生的细胞外囊泡通过抑制SIRT1损害内皮功能。

背景：肺炎克雷伯菌（K.pn）在高血压发展中的潜在作用已得到强调，尽管其具体机制尚未得到很好的理解。革兰氏阴性菌释放的细菌胞外囊泡（BEVs）通过向宿主细胞传递细菌成分来调节宿主细胞功能。内皮功能障碍是高血压发病机制的一个重要早期事件，然而K.pn分泌的EVs （K.pn EVs）对内皮功能的影响尚不清楚。本研究旨在探讨K.pn EVs对内皮功能的影响，并阐明其潜在机制。方法：采用超离心法从菌悬液中分离纯化K.pn EVs，采用透射电镜纳米颗粒跟踪分析和EVs标记物表达进行表征。在体内或体外用K.pn ev治疗后，用钢丝肌图测量内皮依赖性松弛。用共聚焦显微镜测定超氧阴离子的产生，用SA-β-gal活性测定HUVEC的衰老程度。利用SIRT1过表达或激活剂来研究潜在的机制。结果：我们的数据显示K.pn在体内显著损害乙酰胆碱诱导的内皮依赖性松弛和增加内皮细胞超氧阴离子的产生。同样，体内和离体研究表明，K.pn EVs引起明显的内皮功能障碍、内皮刺激和血压升高。进一步的研究发现K.pn EVs降低了内皮细胞中SIRT1和p-eNOS的水平，增加了NOX2、COX-2、ET-1和p53的水平。值得注意的是，SIRT1的过表达或激活可减轻K.pn EVs对内皮细胞的不良反应和蛋白变化。结论：本研究揭示了K.pn EVs在内皮功能障碍中的新作用，并剖析了这一过程的相关机制，有助于从新的视角全面认识K.pn EVs在内皮功能障碍和高血压中的作用。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.