生长分化因子15（GDF15）拮抗作用可限制严重心力衰竭并预防心脏恶病质。
GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
作者信息
Takaoka Minoru, Tadross John A, Al-Hadithi Ali B A K, Zhao Xiaohui, Villena-Gutiérrez Rocío, Tromp Jasper, Absar Shazia, Au Marcus, Harrison James, Coll Anthony P, Marciniak Stefan J, Rimmington Debra, Oliver Eduardo, Ibáñez Borja, Voors Adriaan A, O'Rahilly Stephen, Mallat Ziad, Goodall Jane C
机构信息
Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0QQ, UK.
Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science and Medical Research Council, University of Cambridge, Cambridge, UK.
出版信息
Cardiovasc Res. 2024 Dec 31;120(17):2249-2260. doi: 10.1093/cvr/cvae214.
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.
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整合应激反应（ISR）诱导的eIF2α磷酸酶PPP1R15A的小鼠心力衰竭新模型中导致心脏恶病质的因素。
方法与结果
对小鼠进行照射并用骨髓细胞进行重建。缺乏功能性PPP1R15A的小鼠在照射后表现出扩张型心肌病和严重体重减轻，而野生型小鼠未受影响。这与心脏中Gdf15表达增加和循环中GDF15水平升高有关。我们提供的证据表明，阻断GDF15活性可预防恶病质并减缓心力衰竭的进展。我们还展示了GDF15与心力衰竭患者瘦体重和蛋白质摄入的相关性。
结论
我们的数据表明，心脏应激介导了一条依赖GDF15的途径，该途径导致体重减轻并使心脏功能恶化。阻断GDF15可能构成一种新的治疗选择，以限制心脏恶病质并改善重度收缩性心力衰竭患者的临床结局。
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