Shu Hongyang, Li Na, Zhao Qinqing, Zhang Zixuan, Qin Yating, Nie Jiali, Wang Dao Wen, Zhou Ning
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, 430000, China.
J Transl Med. 2025 Aug 6;23(1):870. doi: 10.1186/s12967-025-06926-0.
Insulin resistance (IR) is an early hallmark of pressure overload-induced myocardial injury and heart failure. Although CD36, a fatty acid transporter, regulates systemic insulin sensitivity, its role in myocardial insulin resistance under pressure overload remains unclear. This study aimed to elucidate CD36's cardioprotective mechanisms in this context.
Myocardial tissues from dilated cardiomyopathy patients, transverse aortic constriction (TAC) mice, and cultured hypertrophic cardiomyocytes were analyzed for CD36 expression and insulin sensitivity. CD36 overexpression was induced via rAAV9-tnt-CD36. InsR-interacting proteins in CD36-overexpressing cells were profiled using tandem mass spectrometry, identifying HSP90α as the key partner. HSP90α agonists were used in rescue experiments. Glucose uptake (2-NBDG assay) and InsR/Akt phosphorylation were measured. Mechanistic studies included immunofluorescence, subcellular fractionation, and HSF1 transcriptional regulation analysis.
CD36 levels and insulin sensitivity were reduced in dilated cardiomyopathy patients, TAC mice, and hypertrophic cardiomyocytes. CD36 overexpression enhanced glucose uptake and insulin signaling. Mass spectrometry identified HSP90α (not HSP90β) as the critical InsR partner modulated by CD36. HSP90α agonists reversed CD36-mediated improvements in glucose uptake and InsR/Akt phosphorylation. Mechanistically, CD36 disrupted HSP90α-InsR binding via (1) HSF1-dependent transcriptional suppression of HSP90α and (2) competitive displacement of HSP90α from InsR. Pathological conditions increased cytosolic InsR-HSP90α trapping, while CD36 redistributed InsR to the plasma membrane.
CD36 mitigates pressure overload-induced insulin resistance by dual mechanisms: suppressing HSP90α expression via HSF1 inhibition and competitively displacing HSP90α to promote InsR membrane localization. This stabilizes insulin signaling and restores metabolic homeostasis, highlighting CD36 as a therapeutic target for heart failure involving metabolic-cardiac crosstalk.
胰岛素抵抗（IR）是压力超负荷诱导的心肌损伤和心力衰竭的早期标志。尽管脂肪酸转运蛋白CD36调节全身胰岛素敏感性，但其在压力超负荷下心肌胰岛素抵抗中的作用仍不清楚。本研究旨在阐明在此背景下CD３６的心脏保护机制。
分析扩张型心肌病患者、横断主动脉缩窄（TAC）小鼠的心肌组织以及培养的肥厚型心肌细胞中的CD36表达和胰岛素敏感性。通过rAAV9-tnt-CD36诱导CD36过表达。使用串联质谱分析CD36过表达细胞中与胰岛素受体（InsR）相互作用的蛋白质，确定热休克蛋白90α（HSP90α）为关键伴侣。在挽救实验中使用HSP90α激动剂。测量葡萄糖摄取（2-NBDG测定）和InsR/Akt磷酸化。机制研究包括免疫荧光、亚细胞分级分离和热休克因子1（HSF1）转录调控分析。
扩张型心肌病患者、TAC小鼠和肥厚型心肌细胞中的CD36水平和胰岛素敏感性降低。CD36过表达增强了葡萄糖摄取和胰岛素信号传导。质谱分析确定HSP90α（而非HSP90β）是受CD36调节的关键InsR伴侣。HSP90α激动剂逆转了CD36介导的葡萄糖摄取和InsR/Akt磷酸化的改善。机制上，CD36通过以下方式破坏HSP90α-InsR结合：（1）HSF1依赖性转录抑制HSP90α；（2）从InsR竞争性取代HSP90α。病理条件增加了细胞质中InsR-HSP90α的捕获，而CD36将InsR重新分布到质膜。
CD36通过双重机制减轻压力超负荷诱导的胰岛素抵抗：通过抑制HSF1来抑制HSP90α表达，并竞争性取代HSP90α以促进InsR膜定位。这稳定了胰岛素信号传导并恢复了代谢稳态，突出了CD36作为涉及代谢-心脏相互作用的心力衰竭治疗靶点的作用。
