Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF.
Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF.
复制标题
骨髓细胞衍生的 IL1β 有助于 HFpEF 中的肺动脉高压。
DOI：
10.1161/circresaha.123.323119
复制
发表时间：
2023
影响因子：
20.1
通讯作者：
Gladson,San
中科院分区：
文献类型：
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作者：
Agrawal,Vineet;Kropski,JonathanA;Gokey,JasonJ;Kobeck,Elizabeth;Murphy,MatthewB;Murray,KatherineT;Fortune,NikiL;Moore,ChristyS;Meoli,DavidF;Monahan,Ken;RuSu,Yan;Blackwell,Thomas;Gupta,DeepakK;Talati,MeghaH;Gladson,San
BACKGROUNDPulmonary 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.METHODSEight-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.RESULTSNγ-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.CONCLUSIONSWe 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.
