Liu Mo-Nan, Liu Zheng-Hong, Leng Rui-Xue, Strijdom Hans, Weng Jian-Ping, Xu Suo-Wen
Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, 230032, China.
Acta Pharmacol Sin. 2025 Apr 30. doi: 10.1038/s41401-025-01561-3.
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-PCSK9 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.
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症的GDF15模拟药物正在进行临床开发。虽然GDF15是体重管理的一个有前景的靶点，但其潜在的心血管作用仍不清楚。在本研究中，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是否既是动脉粥样硬化严重程度的生物标志物又是介质。给载脂蛋白E（ApoE）小鼠喂食高胆固醇饮食（HCD，1.25%胆固醇）6、12或18周以建立动脉粥样硬化模型。我们发现，随着动脉粥样硬化进展，ApoE小鼠血清GDF15水平升高；在冠状动脉疾病患者中也观察到血清GDF15水平升高。受这一发现启发，我们通过注射AAV8-PCSK9病毒并喂食HCD 12或16周，在Gdf15小鼠中建立了动脉粥样硬化模型。我们发现，无论雄性还是雌性小鼠，全身性Gdf15基因敲除均未改变主动脉整体斑块大小、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源性泡沫细胞中，Gdf15缺失或用重组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况，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无显著因果关联。此外，MR研究表明，在英国生物银行和deCODE队列的血浆数据中，GDF15与体重指数（BMI）、载脂蛋白B（ApoB）、低密度脂蛋白（LDL）和高密度脂蛋白（HDL）等因素之间的遗传关联不显著。总之，本研究表明，尽管循环GDF15水平与小鼠和人类疾病进展呈正相关，但全身性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，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。靶向GDF15疗法的长期心血管安全性值得进一步研究。
