骨髓细胞衍生的IL1β参与HFpEF的肺动脉高压。

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2023-11-10 Epub Date: 2023-11-06 DOI:10.1161/CIRCRESAHA.123.323119
Vineet Agrawal, Jonathan A Kropski, Jason J Gokey, Elizabeth Kobeck, Matthew B Murphy, Katherine T Murray, Niki L Fortune, Christy S Moore, David F Meoli, Ken Monahan, Yan Ru Su, Thomas Blackwell, Deepak K Gupta, Megha H Talati, Santhi Gladson, Erica J Carrier, James D West, Anna R Hemnes
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引用次数: 0

摘要

背景:射血分数保留的心力衰竭患者肺动脉高压(PH)是一种常见且高度病态的综合征,但其驱动机制尚不清楚。我们试图确定一个公认的HFpEF小鼠模型是否也显示出PH的特征,并试图确定可能驱动HFpEF肺血管系统早期重塑的途径。方法:8周龄的雄性和雌性C57BL/6J小鼠接受Nγ-硝基-L-精氨酸甲酯和高脂饮食,或对照水和饮食,持续2、5和12周。将db/db小鼠作为HFpEF的第二个模型进行研究。通过大量和单细胞RNA测序鉴定了调节PH的早期途径。通过小鼠肺部的免疫染色或PH-HFpEF患者临床尸检的肺切片证实了这一发现。ELISA用于验证小鼠肺、小鼠血浆以及右心导管插入术时获得的PH-HFpEF患者的人血浆中的IL-1β(IL-1β)。氯膦酸盐脂质体和抗IL-1β抗体分别用于消耗巨噬细胞和IL-1β,以评估它们对小鼠模型中HFpEF中肺血管重塑的影响。结果:Nγ-硝基-L-精氨酸甲酯/高脂饮食治疗的小鼠出现PH、小血管肌肉化和右心功能障碍。炎症相关基因本体在全肺的批量RNA测序分析中过度表达,在小鼠和人类PH-HFpEF肺中CD68+细胞均增加。细胞因子分析显示小鼠和人血浆中IL-1β增加。最后,氯膦酸盐脂质体在小鼠中的治疗阻止了Nγ-硝基-L-精氨酸甲酯/高脂饮食治疗小鼠的PH,IL-1β的耗竭也减弱了Nγ-Noro-L-精胺甲酯/高脂肪饮食治疗小鼠中的PH。结论:我们报道了一种研究HFpEF中PH和右心重构的新模型,我们确定骨髓细胞衍生的IL-1β是HFpEF PH的重要因素。
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Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF.

Background: Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are poorly understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF.

Methods: Eight-week-old male and female C57BL/6J mice received either Nγ-nitro-L-arginine methyl ester and high-fat diet or control water and diet for 2, 5, and 12 weeks. The db/db mice were studied as a second model of HFpEF. Early pathways regulating PH were identified by bulk and single-cell RNA sequencing. Findings were confirmed by immunostain in lungs of mice or lung slides from clinically performed autopsies of patients with PH-HFpEF. ELISA was used to verify IL-1β (interleukin-1 beta) in mouse lung, mouse plasma, and also human plasma from patients with PH-HFpEF obtained at the time of right heart catheterization. Clodronate liposomes and an anti-IL-1β antibody were utilized to deplete macrophages and IL-1β, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF in mouse models.

Results: Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice developed PH, small vessel muscularization, and right heart dysfunction. Inflammation-related gene ontologies were overrepresented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68+ cells in both murine and human PH-HFpEF lungs. Cytokine profiling showed an increase in IL-1β in mouse and human plasma. Finally, clodronate liposome treatment in mice prevented PH in Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice, and IL-1β depletion also attenuated PH in Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice.

Conclusions: We report a novel model for the study of PH and right heart remodeling in HFpEF, and we identify myeloid cell-derived IL-1β as an important contributor to PH in HFpEF.

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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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