Growth differentiation factor 15 protects against diabetic endothelial dysfunction by AMP-activated protein kinase mediation

IF 3.7 3区医学 Q2 PHARMACOLOGY & PHARMACY

Vascular pharmacology Pub Date : 2025-12-01 Epub Date: 2025-10-21 DOI:10.1016/j.vph.2025.107554

Wen Zhao , Yang Liu , Zhengshuo Cui , Xinxin Li, Han Guo, Xueying Chen, Huina Zhang

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引用次数: 0

Abstract

Aims

Endothelial dysfunction is a hallmark of diabetes-associated cardiovascular complications, yet its molecular mechanisms remain incompletely elucidated. Growth differentiation factor 15 (GDF15) has emerged as an important modulator in metabolic and cardiovascular diseases; however, its role in diabetic endothelial dysfunction is poorly understood. This study aims to investigate the therapeutic potential of GDF15 in diabetic endothelial dysfunction and to elucidate the underlying mechanisms.

Methods

db/db mouse aortas or high glucose/high lipid (HG/HL)-treated C57BL/6 mouse aortas were exposed to GDF15 for acute or prolonged durations. Endothelium-dependent relaxation (EDR) was evaluated using wire myography. Meanwhile, western blotting was performed to assess protein levels of nuclear factor erythroid 2-related factor 2 (NRF2), NADPH oxidase 2 (NOX2), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), total AMP-activated protein kinase (AMPK), and phosphorylated AMPK in endothelial cells treated with GDF15 in the presence or absence of HG/HL. Reactive oxygen species (ROS) production in en face endothelial cells of mouse aortas was measured via confocal microscopy.

Results

Exogenous GDF15 acute or prolonged administration markedly ameliorated HG/HL- and diabetes-induced endothelial dysfunction and excess reactive oxygen species (ROS) generation. Meanwhile, GDF15 counteracted HG/HL-induced changes in NOX2, NRF2, ACE, and ACE2 protein expression in endothelial cells. These beneficial effects of GDF15 were mechanistically linked to AMPK upregulation, as evidenced by elevated AMPK levels in GDF15-treated endothelial cells, and the suppression of GDF15's vasoprotective effects by the AMPK inhibitor Compound C.

Conclusions

Our findings demonstrate that GDF15 ameliorates diabetic endothelial dysfunction and oxidative stress by AMPK-dependent pathways in endothelial cells. These results highlight GDF15 as a promising therapeutic target for mitigating oxidative stress and preserving diabetic endothelial dysfunction.

Abstract Image

查看原文本刊更多论文

生长分化因子15通过amp激活的蛋白激酶介导糖尿病内皮功能障碍。

目的：内皮功能障碍是糖尿病相关心血管并发症的一个标志，但其分子机制仍未完全阐明。生长分化因子15 （GDF15）已成为代谢和心血管疾病的重要调节剂；然而，其在糖尿病内皮功能障碍中的作用尚不清楚。本研究旨在探讨GDF15在糖尿病内皮功能障碍中的治疗潜力，并阐明其潜在机制。方法：将db/db小鼠主动脉或HG/HL处理的C57BL/6小鼠主动脉急性或长时间暴露于GDF15。内皮依赖性松弛（EDR）采用钢丝肌图评估。同时，采用western blotting检测在HG/HL存在或不存在的情况下，GDF15处理的内皮细胞中核因子-红细胞2相关因子2 （NRF2）、NADPH氧化酶2 （NOX2）、血管紧张素转换酶（ACE）、血管紧张素转换酶2 （ACE2）、总amp活化蛋白激酶（AMPK）和磷酸化AMPK的蛋白水平。用共聚焦显微镜观察小鼠主动脉表面内皮细胞活性氧（ROS）的产生。结果：外源性GDF15急性或长期给药可显著改善HG/HL和糖尿病诱导的内皮功能障碍和过量活性氧（ROS）的产生。同时，GDF15可以抵消HG/ hl诱导的内皮细胞中NOX2、NRF2、ACE和ACE2蛋白表达的变化。GDF15的这些有益作用在机制上与AMPK上调有关，如GDF15处理的内皮细胞中AMPK水平升高，以及AMPK抑制剂化合物c抑制GDF15的血管保护作用。结论：我们的研究结果表明，GDF15通过内皮细胞中AMPK依赖的途径改善了糖尿病内皮功能障碍和氧化应激。这些结果突出了GDF15作为减轻氧化应激和保护糖尿病内皮功能障碍的有希望的治疗靶点。

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

Vascular pharmacology 医学-药学

CiteScore

6.60

自引率

2.50%

发文量

153

审稿时长

31 days

期刊介绍： Vascular Pharmacology publishes papers, which contains results of all aspects of biology and pharmacology of the vascular system. Papers are encouraged in basic, translational and clinical aspects of Vascular Biology and Pharmacology, utilizing approaches ranging from molecular biology to integrative physiology. All papers are in English. The Journal publishes review articles which include vascular aspects of thrombosis, inflammation, cell signalling, atherosclerosis, and lipid metabolism.