Fibroblast growth factor 21 improves diabetic cardiomyopathy by inhibiting ferroptosis via ferritin pathway.

IF 8.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Ruxin Wang, Xiaofang Zhang, Haowen Ye, Xian Yang, Yongting Zhao, Liangyan Wu, Han Liu, Yun Wen, Jiaxin Wang, Ying Wang, Meixin Yu, Caixia Ma, Lihong Wang
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Abstract

Background: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 2 diabetes mellitus, and its mechanisms are complex and poorly understood. Despite growing evidence suggesting that ferroptosis plays a significant role in cardiovascular disease, it has been less extensively studied in DCM. Fibroblast growth factor 21 (FGF21), whose mechanism of action is closely related to ferroptosis, is widely utilized in studies focused on the prevention and treatment of glucolipid metabolism-related diseases and cardiovascular diseases.

Objective: To confirm the significant role of ferroptosis in DCM and to investigate whether FGF21 improves DCM by inhibiting ferroptosis and elucidating its specific molecular mechanisms.

Methods: The animal DCM models were established through high-fat feeding combined with streptozotocin injection in C57BL/6J mice or by db/db mice, and the diabetic cardiomyocyte injury model was created using high glucose and high fat (HG/HF) culture of primary cardiomyocytes. Intervention modeling of FGF21 were performed by injecting adeno-associated virus 9-FGF21 in mice and transfecting FGF21 siRNA or overexpression plasmid in primary cardiomyocytes.

Results: The findings indicated that ferroptosis was exacerbated and played a significant role in DCM. The overexpression of FGF21 inhibited ferroptosis and improved cardiac injury and function, whereas the knockdown of FGF21 aggravated ferroptosis and cardiac injury and function in DCM. Furthermore, we discovered that FGF21 inhibited ferroptosis in DCM by directly acting on ferritin and prolonging its half-life. Specifically, FGF21 binded to the heavy and light chains of ferritin, thereby reducing its excessive degradation in the proteasome and lysosomal-autophagy pathways in DCM. Additionally, activating transcription factor 4 (ATF4) served as the upstream regulator of FGF21 in DCM.

Conclusions: The ATF4-FGF21-ferritin axis mediates the protective effects in DCM through the ferroptosis pathway and represents a potential therapeutic target for DCM.

成纤维细胞生长因子 21 通过铁蛋白途径抑制铁蛋白沉积,从而改善糖尿病心肌病。
背景:糖尿病心肌病(DCM)是 2 型糖尿病患者的一种严重并发症,其发病机制复杂,人们对其了解甚少。尽管越来越多的证据表明,铁蛋白沉积在心血管疾病中起着重要作用,但对其在 DCM 中的作用却研究较少。成纤维细胞生长因子 21(FGF21)的作用机制与铁蛋白沉积密切相关,被广泛用于预防和治疗糖脂代谢相关疾病和心血管疾病的研究中:目的:证实铁蛋白沉积在 DCM 中的重要作用,并研究 FGF21 是否能通过抑制铁蛋白沉积来改善 DCM,同时阐明其具体的分子机制:C57BL/6J小鼠或db/db小鼠通过高脂喂养联合链脲佐菌素注射建立动物DCM模型,利用高糖高脂(HG/HF)培养原代心肌细胞建立糖尿病心肌细胞损伤模型。通过在小鼠体内注射腺相关病毒 9-FGF21,以及在原代心肌细胞中转染 FGF21 siRNA 或过表达质粒,对 FGF21 进行干预建模:结果:研究结果表明,铁突变在 DCM 中加剧并发挥重要作用。过表达 FGF21 可抑制铁蛋白沉积,改善心脏损伤和功能,而敲除 FGF21 则会加重铁蛋白沉积,加重 DCM 的心脏损伤和功能。此外,我们还发现 FGF21 通过直接作用于铁蛋白并延长其半衰期来抑制 DCM 的铁蛋白沉积。具体来说,FGF21 与铁蛋白的重链和轻链结合,从而减少了铁蛋白在蛋白酶体和溶酶体-自噬途径中的过度降解。此外,激活转录因子4(ATF4)是DCM中FGF21的上游调节因子:ATF4-FGF21-铁蛋白轴通过铁蛋白沉积途径介导了DCM的保护作用,是DCM的潜在治疗靶点。
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来源期刊
Cardiovascular Diabetology
Cardiovascular Diabetology 医学-内分泌学与代谢
CiteScore
12.30
自引率
15.10%
发文量
240
审稿时长
1 months
期刊介绍: Cardiovascular Diabetology is a journal that welcomes manuscripts exploring various aspects of the relationship between diabetes, cardiovascular health, and the metabolic syndrome. We invite submissions related to clinical studies, genetic investigations, experimental research, pharmacological studies, epidemiological analyses, and molecular biology research in this field.
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