IF 35.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Mallory Filipp, Zhi-Dong Ge, Matthew DeBerge, Connor Lantz, Kristofor Glinton, Peng Gao, Sasha Smolgovsky, Jingbo Dai, You-Yang Zhao, Laurent Yvan-Charvet, Pilar Alcaide, Samuel E Weinberg, Gabriele G Schiattarella, Joseph A Hill, Matthew J Feinstein, Sanjiv J Shah, Edward B Thorp
{"title":"Myeloid Fatty Acid Metabolism Activates Neighboring Hematopoietic Stem Cells to Promote Heart Failure With Preserved Ejection Fraction.","authors":"Mallory Filipp, Zhi-Dong Ge, Matthew DeBerge, Connor Lantz, Kristofor Glinton, Peng Gao, Sasha Smolgovsky, Jingbo Dai, You-Yang Zhao, Laurent Yvan-Charvet, Pilar Alcaide, Samuel E Weinberg, Gabriele G Schiattarella, Joseph A Hill, Matthew J Feinstein, Sanjiv J Shah, Edward B Thorp","doi":"10.1161/CIRCULATIONAHA.124.070248","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Despite the high morbidity and mortality of heart failure with preserved ejection fraction (HFpEF), treatment options remain limited. The HFpEF syndrome is associated with a high comorbidity burden, including high prevalence of obesity and hypertension. Although inflammation is implicated to play a key role in HFpEF pathophysiology, underlying causal mechanisms remain unclear.</p><p><strong>Methods: </strong>Comparing patient samples and animal models, we defined the innate immune response during HFpEF in situ and through flow cytometry and single-cell RNA sequencing. After identifying transcriptional and cell signatures, we implemented a high-fat diet and hypertensive model of HFpEF and tested roles for myeloid and hematopoietic stem cells during HFpEF. Contributions of macrophage metabolism were also evaluated, including through mass spectrometry and carbon labeling. Primary macrophages were studied ex vivo to gain insight into complementary cell-intrinsic mechanisms.</p><p><strong>Results: </strong>Here we report evidence that patients with cardiometabolic HFpEF exhibit elevated peripheral blood hematopoietic stem cells. This phenotype was conserved across species in a murine mode of high-fat diet and hypertension. Hematopoietic stem cell proliferation was coupled to striking remodeling of the peripheral hematopoietic stem cell niche and expression of the macrophage adhesion molecule <i>Vcam1</i>. This could be partially inhibited by sodium-glucose cotransporter-2 inhibitors and explained by elevated fatty acid metabolism in macrophage mitochondria, which in turn remodeled the <i>Vcam1</i> promoter to enhance its expression.</p><p><strong>Conclusions: </strong>These findings identify a significant new stem cell signature of cardiometabolic HFpEF and support a role for myeloid maladaptive fatty acid metabolism in the promotion of systemic inflammation and cardiac diastolic dysfunction.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5000,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCULATIONAHA.124.070248","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0

摘要

背景:尽管射血分数保留型心力衰竭(HFpEF)的发病率和死亡率很高,但治疗方案仍然有限。高射血分数(HFpEF)综合征具有较高的并发症负担,包括高肥胖率和高血压。尽管炎症被认为在 HFpEF 病理生理学中起着关键作用,但其潜在的因果机制仍不清楚:方法:通过比较患者样本和动物模型,我们在原位并通过流式细胞术和单细胞 RNA 测序确定了 HFpEF 期间的先天性免疫反应。在确定转录和细胞特征后,我们实施了高脂饮食和高血压的HFpEF模型,并测试了骨髓和造血干细胞在HFpEF期间的作用。我们还通过质谱和碳标记等方法评估了巨噬细胞新陈代谢的贡献。对原代巨噬细胞进行了体外研究,以深入了解细胞内在互补机制:结果:在此,我们报告了心脏代谢性高频低氧血症患者外周血造血干细胞升高的证据。在高脂饮食和高血压的小鼠模式中,这种表型在不同物种间保持一致。造血干细胞增殖与外周血造血干细胞龛位的显著重塑和巨噬细胞粘附分子Vcam1的表达有关。钠-葡萄糖共转运体-2抑制剂可部分抑制这一现象,而巨噬细胞线粒体中脂肪酸代谢的升高反过来又重塑了Vcam1启动子,增强了其表达:这些研究结果确定了心脏代谢性高频低氧血症(HFpEF)的一个重要的新干细胞特征,并支持髓系不适应性脂肪酸代谢在促进全身炎症和心脏舒张功能障碍中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Myeloid Fatty Acid Metabolism Activates Neighboring Hematopoietic Stem Cells to Promote Heart Failure With Preserved Ejection Fraction.

Background: Despite the high morbidity and mortality of heart failure with preserved ejection fraction (HFpEF), treatment options remain limited. The HFpEF syndrome is associated with a high comorbidity burden, including high prevalence of obesity and hypertension. Although inflammation is implicated to play a key role in HFpEF pathophysiology, underlying causal mechanisms remain unclear.

Methods: Comparing patient samples and animal models, we defined the innate immune response during HFpEF in situ and through flow cytometry and single-cell RNA sequencing. After identifying transcriptional and cell signatures, we implemented a high-fat diet and hypertensive model of HFpEF and tested roles for myeloid and hematopoietic stem cells during HFpEF. Contributions of macrophage metabolism were also evaluated, including through mass spectrometry and carbon labeling. Primary macrophages were studied ex vivo to gain insight into complementary cell-intrinsic mechanisms.

Results: Here we report evidence that patients with cardiometabolic HFpEF exhibit elevated peripheral blood hematopoietic stem cells. This phenotype was conserved across species in a murine mode of high-fat diet and hypertension. Hematopoietic stem cell proliferation was coupled to striking remodeling of the peripheral hematopoietic stem cell niche and expression of the macrophage adhesion molecule Vcam1. This could be partially inhibited by sodium-glucose cotransporter-2 inhibitors and explained by elevated fatty acid metabolism in macrophage mitochondria, which in turn remodeled the Vcam1 promoter to enhance its expression.

Conclusions: These findings identify a significant new stem cell signature of cardiometabolic HFpEF and support a role for myeloid maladaptive fatty acid metabolism in the promotion of systemic inflammation and cardiac diastolic dysfunction.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Circulation
Circulation 医学-外周血管病
CiteScore
45.70
自引率
2.10%
发文量
1473
审稿时长
2 months
期刊介绍: Circulation is a platform that publishes a diverse range of content related to cardiovascular health and disease. This includes original research manuscripts, review articles, and other contributions spanning observational studies, clinical trials, epidemiology, health services, outcomes studies, and advancements in basic and translational research. The journal serves as a vital resource for professionals and researchers in the field of cardiovascular health, providing a comprehensive platform for disseminating knowledge and fostering advancements in the understanding and management of cardiovascular issues.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信