Revisiting the role of GDF15 in atherosclerosis in mouse and human.

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Mo-Nan Liu, Zheng-Hong Liu, Rui-Xue Leng, Hans Strijdom, Jian-Ping Weng, Suo-Wen Xu
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引用次数: 0

Abstract

Growth differentiation factor 15 (GDF15) is a key regulator of food intake and energy metabolism. GDF15 mimetic drugs for the treatment of metabolic syndrome and obesity are under clinical development. While GDF15 presents a promising target for weight management, its potential cardiovascular actions remain elusive. In this study we investigated the role of GDF15 in macrophage function and atherosclerosis pathogenesis and whether GDF15 acts both as a biomarker and mediator of atherosclerosis severity. ApoE-/- mice were fed a high-cholesterol diet (HCD, 1.25% cholesterol) for 6, 12 or 18 weeks to establish atherosclerotic models. We showed that serum levels of GDF15 were elevated in ApoE-/- mice with atheroprogression; increased serum levels of GDF15 were also observed in patients with coronary artery disease. Enlightened by this finding, we established atherosclerotic model in Gdf15-/- mice by injecting with AAV8-PCSK9D377Y virus and feeding HCD for 12 or 16 weeks. We showed that global Gdf15 knockout, whether in male or female mice, did not alter plaque size in en face aorta, lesion in aortic sinus, size of necrotic core or plaque composition. In macrophage-derived foam cells isolated from atherosclerotic mice, neither Gdf15 deletion nor the treatment with recombinant GDF15 protein (1, 10, 100 ng/mL) affected lipid deposition or macrophage polarization. To translate this finding into a clinically relevant scenario, we performed Mendelian randomization (MR) analysis, and found no significant causal association between circulating GDF15 levels and the incidence of cardiovascular diseases. Furthermore, MR studies suggest that genetic associations between GDF15 and factors such as BMI, ApoB, LDL and HDL were not significant in plasma data from the UK Biobank and the deCODE cohort. In summary, this study demonstrates that global Gdf15 deficiency does not affect the development of atherosclerosis in male or female mice despite the positive association between circulating GDF15 levels and disease progression in mice and human. Thus, GDF15 in circulation is a potential biomarker, but not a causal mediator, of atherosclerosis. Long-term cardiovascular safety of GDF15-targeted therapies warrants further investigation.

GDF15在小鼠和人动脉粥样硬化中的作用。
生长分化因子15 (GDF15)是食物摄入和能量代谢的关键调节因子。用于治疗代谢综合征和肥胖的仿GDF15药物正在临床开发中。虽然GDF15为体重管理提供了一个有希望的目标,但其潜在的心血管作用仍然难以捉摸。在这项研究中,我们研究了GDF15在巨噬细胞功能和动脉粥样硬化发病机制中的作用,以及GDF15是否作为动脉粥样硬化严重程度的生物标志物和中介。ApoE-/-小鼠分别饲喂高胆固醇饮食(HCD, 1.25%胆固醇)6、12或18周,建立动脉粥样硬化模型。我们发现ApoE-/-动脉粥样硬化小鼠血清GDF15水平升高;冠状动脉疾病患者血清GDF15水平也升高。受此启发,我们通过注射AAV8-PCSK9D377Y病毒并喂养HCD 12或16周,建立了Gdf15-/-小鼠动脉粥样硬化模型。我们发现,无论在雄性还是雌性小鼠中,Gdf15基因敲除都不会改变正面主动脉斑块大小、主动脉窦病变、坏死核心大小或斑块组成。在从动脉粥样硬化小鼠分离的巨噬细胞来源的泡沫细胞中,Gdf15缺失和重组Gdf15蛋白(1、10、100 ng/mL)处理均不影响脂质沉积或巨噬细胞极化。为了将这一发现转化为临床相关情景,我们进行了孟德尔随机化(MR)分析,发现循环GDF15水平与心血管疾病发病率之间没有显著的因果关系。此外,MR研究表明,在UK Biobank和deCODE队列的血浆数据中,GDF15与BMI、ApoB、LDL和HDL等因素之间的遗传关联并不显著。总之,本研究表明,尽管在小鼠和人类中,循环Gdf15水平与疾病进展呈正相关,但全球Gdf15缺乏并不影响雄性或雌性小鼠动脉粥样硬化的发展。因此,血液循环中的GDF15是动脉粥样硬化的潜在生物标志物,但不是因果介质。gdf15靶向治疗的长期心血管安全性有待进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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