Myeloid Cell Derived IL1β Contributes to Pulmonary Vascular Remodeling in Heart Failure with Preserved Ejection Fraction.
Myeloid Cell Derived IL1β Contributes to Pulmonary Vascular Remodeling in Heart Failure with Preserved Ejection Fraction.
复制标题
骨髓细胞衍生的 IL1β 有助于心力衰竭的肺血管重塑，并保留射血分数。
DOI：
10.1101/2023.05.18.541302
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Gladson,Santh
中科院分区：
文献类型：
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作者：
Agrawal,Vineet;Kropski,JonathanA;Gokey,JasonJ;Kobeck,Elizabeth;Murphy,Matthew;Murray,KatherineT;Fortune,NikiL;Moore,ChristyS;Meoli,DavidF;Monahan,Ken;Su,YanRu;Blackwell,Thomas;Gupta,DeepakK;Talati,MeghaH;Gladson,Santh
射血分数保留性心力衰竭（HFpEF）合并肺动脉高压（PH）是一种常见且高度病态的综合征，但PH-HFpEF的发生机制尚不清楚。我们试图确定是否一个广为接受的HFpEF小鼠模型也显示在HFpEF的PH功能，我们试图确定的途径，可能会推动早期重建的肺血管HFpEF.MethodsEight周龄的男性和女性C57/BL 6 J小鼠给予L-NAME和高脂肪饮食（HFD）或控制水/饮食2，5，和12周。进行批量RNA测序和单细胞RNA测序以鉴定可能调节PH-HFpEF中肺血管重构的早期和细胞特异性途径。最后，氯膦酸盐脂质体和IL 1 β抗体治疗被用来消耗巨噬细胞或IL 1 β，分别评估其对HFpEF. ResultsL-NAME/HFD小鼠肺血管重构的影响开发PH，小血管肌化，右心功能障碍治疗2周后。炎症相关基因本体在全肺的批量RNA测序分析中过度表达，在鼠和人PH-HFpEF肺中CD 68+细胞均增加。小鼠肺和血浆的细胞因子谱显示IL 1 β增加，这在HFpEF患者的血浆中得到证实。小鼠肺的单细胞测序也显示Ccr 2+单核细胞和巨噬细胞的M1样促炎群体增加，IL 1 β的转录表达主要限于骨髓型细胞。最后，氯膦酸盐脂质体治疗阻止了L-NAME/HFD治疗小鼠PH的发展，IL 1 β抗体治疗也减弱了L-NAME/HFD治疗mice.ConclusionsOur study demonstrated that a well-accepted model of HFpEF recapitulates features of pulmonary vascular remodeling commonly seen in patients with HFpEF，and we identified myeloid cell derived IL 1 β as a important contributor to PH in HFpEF.
BackgroundPulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are not well understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH in HFpEF, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF.MethodsEight week old male and female C57/BL6J mice were given either L-NAME and high fat diet (HFD) or control water/diet for 2,5, and 12 weeks. Bulk RNA sequencing and single cell RNA sequencing was performed to identify early and cell-specific pathways that might regulate pulmonary vascular remodeling in PH-HFpEF. Finally, clodronate liposome and IL1β antibody treatments were utilized to deplete macrophages or IL1β, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF.ResultsMice given L-NAME/HFD developed PH, small vessel muscularization, and right heart dysfunction after 2 weeks of treatment. Inflammation-related gene ontologies were over-represented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68+ cells in both murine and human PH-HFpEF lungs. Cytokine profiling of mouse lung and plasma showed an increase in IL1β, which was confirmed in plasma from patients with HFpEF. Single cell sequencing of mouse lungs also showed an increase in M1-like, pro-inflammatory populations of Ccr2+ monocytes and macrophages, and transcript expression of IL1β was primarily restricted to myeloid-type cells. Finally, clodronate liposome treatment prevented the development of PH in L-NAME/HFD treated mice, and IL1β antibody treatment also attenuated PH in L-NAME/HFD treated mice.ConclusionsOur study demonstrated that a well-accepted model of HFpEF recapitulates features of pulmonary vascular remodeling commonly seen in patients with HFpEF, and we identified myeloid cell derived IL1β as an important contributor to PH in HFpEF.