GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.

IF 10.2 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Cardiovascular Research Pub Date : 2024-09-23 DOI:10.1093/cvr/cvae214

Minoru Takaoka, John A Tadross, Ali B A K Al-Hadithi, Xiaohui Zhao, Rocío Villena-Gutiérrez, Jasper Tromp, Shazia Absar, Marcus Au, James Harrison, Anthony P Coll, Stefan J Marciniak, Debra Rimmington, Eduardo Oliver, Borja Ibáñez, Adriaan A Voors, Stephen O'Rahilly, Ziad Mallat, Jane C Goodall

{"title":"GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.","authors":"Minoru Takaoka, John A Tadross, Ali B A K Al-Hadithi, Xiaohui Zhao, Rocío Villena-Gutiérrez, Jasper Tromp, Shazia Absar, Marcus Au, James Harrison, Anthony P Coll, Stefan J Marciniak, Debra Rimmington, Eduardo Oliver, Borja Ibáñez, Adriaan A Voors, Stephen O'Rahilly, Ziad Mallat, Jane C Goodall","doi":"10.1093/cvr/cvae214","DOIUrl":null,"url":null,"abstract":"Aims: Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A.Methods and results: Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure.Conclusion: Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2000,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardiovascular Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/cvr/cvae214","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

Abstract

Aims: Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A.

Methods and results: Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure.

Conclusion: Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.

查看原文本刊更多论文

GDF15 拮抗剂可限制严重心力衰竭并防止心脏恶病质。

目的：心力衰竭及相关恶病质是一个尚未解决的重要问题。本研究旨在确定在缺乏综合应激反应（ISR）诱导的 eIF2α 磷酸酶 PPP1R15A 的心力衰竭小鼠新模型中导致心脏恶病质的因素：对小鼠进行辐照并用骨髓细胞进行重组。缺乏功能性 PPP1R15A 的小鼠在辐照后表现出扩张型心肌病和严重的体重减轻，而野生型小鼠则不受影响。这与心脏中 Gdf15 的表达增加和血液循环中 GDF15 水平的增加有关。我们提供的证据表明，阻断 GDF15 的活性可以防止恶病质并减缓心力衰竭的进展。我们还显示了 GDF15 与心力衰竭患者瘦体重和蛋白质摄入量的相关性：我们的数据表明，心脏应激介导了一条依赖于 GDF15 的途径，该途径促使体重减轻并恶化心脏功能。阻断 GDF15 可作为一种新的治疗选择，以限制心脏恶病质并改善严重收缩性心力衰竭患者的临床预后。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cardiovascular Research 医学-心血管系统

CiteScore

21.50

自引率

3.70%

发文量

547

审稿时长

1 months

期刊介绍： Cardiovascular Research Journal Overview: International journal of the European Society of Cardiology Focuses on basic and translational research in cardiology and cardiovascular biology Aims to enhance insight into cardiovascular disease mechanisms and innovation prospects Submission Criteria: Welcomes papers covering molecular, sub-cellular, cellular, organ, and organism levels Accepts clinical proof-of-concept and translational studies Manuscripts expected to provide significant contribution to cardiovascular biology and diseases