β-Sitosterol suppresses NLRP3 Inflammasome activation and Pyroptosis in myocardial ischemia/reperfusion injury via inhibition of PPARγ2

IF 4.7 2区医学 Q2 IMMUNOLOGY International immunopharmacology Pub Date : 2025-05-08 Epub Date: 2025-03-28 DOI:10.1016/j.intimp.2025.114543

Zheyi Wu , Niwen Huang , Chao Li , Muzhi Lin , Zhangrong Chen , Wei Li , Haiyan Zhou

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Abstract

Background

β-Sitosterol, a plant-derived sterol, has demonstrated potential therapeutic effects in cardiovascular diseases, particularly myocardial ischemia-reperfusion injury (MIRI). Our study investigates its underlying mechanism through regulation of pyroptosis.

Methods

To understand the role of β-sitosterol in protecting cardiomyocytes, MIRI rats were treated with β-sitosterol. Rats' cardiac functions were monitored, and hearts were harvested for histology and Western Blot analysis. Immunofluorescence, immunoblot, enzyme-linked immunosorbent assay, as well as overexpression and knockdown techniques were utilized in this study to investigate the molecular mechanisms underlying the cardioprotective effects of β-sitosterol.

Results

Our results showed that β-Sitosterol significantly reduced H/R-induced pyroptosis in cardiomyocytes by decreasing cleaved caspase-1, gasdermin D (GSDMD), interleukin-1β (IL-1β), and interleukin-18 (IL-18). Immunofluorescence staining confirmed suppression of NLRP3 inflammasome activation. Notably, β-Sitosterol inhibited pyroptosis induced by ATP and ATP/LPS through the regulation of PPARγ2. Moreover, PPARγ2 upregulation promoted ATP and ATP/LPS-induced pyroptosis through the NLRP3/caspase-1/GSDMD pathway. In vivo, β-sitosterol alleviates myocardial ischemia-reperfusion injury-induced cardiac dysfunction and myocardial fibrosis in rats.

Conclusions

These findings provide new evidence supporting β-sitosterol as a potential therapeutic agent for cardiovascular diseases involving ischemic injury. Its protective effects may be mediated through targeting PPARγ2 and modulating NLRP3-dependent pyroptosis.

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β-谷甾醇通过抑制ppar γ - 2抑制心肌缺血/再灌注损伤NLRP3炎性体激活和焦亡

β-谷甾醇是一种植物来源的甾醇，已被证明对心血管疾病，特别是心肌缺血再灌注损伤（MIRI）有潜在的治疗作用。我们的研究通过对焦亡的调控来探讨其潜在的机制。方法为了解β-谷甾醇对心肌细胞的保护作用，采用β-谷甾醇治疗MIRI大鼠。监测大鼠心功能，采集心脏进行组织学和Western Blot分析。本研究利用免疫荧光、免疫印迹、酶联免疫吸附试验以及过表达和敲低技术来研究β-谷甾醇心脏保护作用的分子机制。结果β-谷甾醇通过降低裂解caspase-1、gasdermin D （GSDMD）、白细胞介素-1β (IL-1β)和白细胞介素-18 (IL-18)，显著降低H/ r诱导的心肌细胞焦亡。免疫荧光染色证实NLRP3炎性体活化受到抑制。值得注意的是，β-谷甾醇通过调控ppar γ - 2抑制ATP和ATP/LPS诱导的焦亡。此外，ppar γ - 2上调通过NLRP3/caspase-1/GSDMD途径促进ATP和ATP/ lps诱导的焦亡。在体内，β-谷甾醇可减轻大鼠心肌缺血再灌注损伤引起的心功能障碍和心肌纤维化。结论β-谷甾醇可作为缺血性心血管疾病的潜在治疗药物。其保护作用可能通过靶向ppar γ - 2和调节nlrp3依赖性焦亡介导。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.