ESCRT-III 组件 CHMP4C 通过靶向 EGFR 的内体溶酶体降解来减弱心肌肥厚。
ESCRT-III Component CHMP4C Attenuates Cardiac Hypertrophy by Targeting the Endo-Lysosomal Degradation of EGFR.
机构信息
Department of Echocardiography (A.L., H.X., F.T., H.W., Y.L., W.L., L.T., N.Z., X.S.), Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China.
Department of Cardiology (A.L., H.X., P.B., H.W., X.S.), Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China.
出版信息
Hypertension. 2023 Dec;80(12):2674-2686. doi: 10.1161/HYPERTENSIONAHA.123.21427. Epub 2023 Oct 17.
BACKGROUND
Cardiac hypertrophy and subsequent heart failure impose a considerable burden on public health worldwide. Impaired protein degradation, especially endo-lysosome-mediated degradation of membrane proteins, is associated with cardiac hypertrophy progression. CHMP4C (charged multivesicular body protein 4C), a critical constituent of multivesicular bodies, is involved in cellular trafficking and signaling. However, the specific role of CHMP4C in the progression of cardiac hypertrophy remains largely unknown.
METHODS
Mouse models with CHMP4C knockout or cardiadc-specific overexpression were subjected to transverse aortic constriction surgery for 4 weeks. Cardiac morphology and function were assessed through histological staining and echocardiography. Confocal imaging and coimmunoprecipitation assays were performed to identify the direct target of CHMP4C. An EGFR (epidermal growth factor receptor) inhibitor was administrated to determine whether effects of CHMP4C on cardiac hypertrophy were EGFR dependent.
RESULTS
CHMP4C was significantly upregulated in both pressure-overloaded mice and spontaneously hypertensive rats. Compared with wild-type mice, CHMP4C deficiency exacerbated transverse aortic constriction-induced cardiac hypertrophy, whereas CHMP4C overexpression in cardiomyocytes attenuated cardiac dysfunction. Mechanistically, the effect of CHMP4C on cardiac hypertrophy relied on the EGFR signaling pathway. Fluorescent staining and coimmunoprecipitation assays confirmed that CHMP4C interacts directly with EGFR and promotes lysosome-mediated degradation of activated EGFR, thus attenuating cardiac hypertrophy. Notably, an EGFR inhibitor canertinib counteracted the exacerbation of cardiac hypertrophy induced by CHMP4C knockdown in vitro and in vivo.
CONCLUSIONS
CHMP4C represses cardiac hypertrophy by modulating lysosomal degradation of EGFR and is a potential therapeutic candidate for cardiac hypertrophy.
背景
心肌肥厚及随后的心力衰竭给全球公共健康带来了巨大负担。蛋白降解受损，特别是膜蛋白的内溶酶体介导的降解，与心肌肥厚的进展有关。CHMP4C（多泡体相关蛋白 4C）是多泡体的关键组成部分，参与细胞运输和信号转导。然而，CHMP4C 在心肌肥厚进展中的具体作用在很大程度上仍不清楚。
方法
通过横主动脉缩窄术对 CHMP4C 敲除或心脏特异性过表达的小鼠模型进行 4 周处理。通过组织学染色和超声心动图评估心脏形态和功能。通过共聚焦成像和免疫共沉淀实验来确定 CHMP4C 的直接靶标。给予表皮生长因子受体（EGFR）抑制剂以确定 CHMP4C 对心肌肥厚的影响是否依赖于 EGFR。
结果
CHMP4C 在压力超负荷小鼠和自发性高血压大鼠中均显著上调。与野生型小鼠相比，CHMP4C 缺陷加剧了横主动脉缩窄诱导的心肌肥厚，而心肌细胞中过表达 CHMP4C 则减轻了心脏功能障碍。从机制上讲，CHMP4C 对心肌肥厚的影响依赖于 EGFR 信号通路。荧光染色和免疫共沉淀实验证实，CHMP4C 与 EGFR 直接相互作用，并促进激活的 EGFR 溶酶体介导的降解，从而减轻心肌肥厚。值得注意的是，EGFR 抑制剂卡那替尼在体外和体内均能拮抗 CHMP4C 敲低诱导的心肌肥厚加重。
结论
CHMP4C 通过调节 EGFR 的溶酶体降解来抑制心肌肥厚，是心肌肥厚的潜在治疗候选物。
Zotero 插件