Department of Endocrinology and Metabolism, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China.
Department of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
Cardiovasc Diabetol. 2024 Nov 2;23(1):394. doi: 10.1186/s12933-024-02469-8.
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.
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.
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.
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.
The ATF4-FGF21-ferritin axis mediates the protective effects in DCM through the ferroptosis pathway and represents a potential therapeutic target for DCM.
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，尚未完全阐明。尽管越来越多的证据表明铁死亡在心血管疾病中起重要作用，但在 DCM 中的研究还不够广泛。成纤维细胞生长因子 21（FGF21）的作用机制与铁死亡密切相关，在研究预防和治疗糖脂代谢相关疾病和心血管疾病方面被广泛应用。
证实铁死亡在 DCM 中的重要作用，并探讨 FGF21 是否通过抑制铁死亡来改善 DCM 及其具体的分子机制。
通过高脂喂养联合链脲佐菌素（STZ）注射构建 C57BL/6J 小鼠 DCM 模型，或 db/db 小鼠构建糖尿病心肌病模型，高糖高脂（HG/HF）培养原代心肌细胞构建糖尿病心肌细胞损伤模型，通过尾静脉注射腺相关病毒 9-FGF21 在小鼠体内进行 FGF21 的干预造模，或通过转染 FGF21 siRNA 或过表达质粒在原代心肌细胞中进行 FGF21 的干预。
研究结果表明，铁死亡在 DCM 中加剧并发挥重要作用。FGF21 的过表达抑制铁死亡，改善心脏损伤和功能，而 FGF21 的敲低加剧 DCM 中的铁死亡和心脏损伤及功能。此外，我们发现 FGF21 通过直接作用于铁蛋白并延长其半衰期来抑制 DCM 中的铁死亡。具体来说，FGF21 与铁蛋白的重链和轻链结合，从而减少 DCM 中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-铁蛋白轴通过铁死亡途径介导 DCM 的保护作用，是 DCM 的潜在治疗靶点。
