Clinical Research Institute, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, China; Department of Cardiovascular Medicine, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, Clinical Medicine Research Center of Arteriosclerotic Disease of Hunan Province, Hengyang, 421002, Hunan, China.
Department of Cardiovascular Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, China.
Eur J Pharmacol. 2022 Jun 5;924:174980. doi: 10.1016/j.ejphar.2022.174980. Epub 2022 Apr 26.
Hypertrophic cardiomyopathy (HC) is characterized by the enlargement of individual cardiomyocytes, which is a typical pathophysiological process that occurs in various cardiovascular diseases. Ionizing radiation (IR) is an important independent risk factor for hypertrophic cardiomyopathy, but the underlying molecular mechanism is still unclear. In the present study, we aimed to clarify the role of IR in promoting cardiac hypertrophy and investigate the mechanism by which the SUMO2-mediated SUMOylation of SH3GLB1 affects mitophagy in IR-induced cardiac hypertrophy. In vivo, IR promoted cardiac hypertrophy by activating mitophagy. In vitro, IR upregulated PINK1 and Parkin protein expression and damaged mitochondrial morphological structure. We further demonstrated that SH3GLB1 deficiency inhibited mitophagy activation and restored mitochondrial cristae, revealing a regulatory role of SH3GLB1 in cardiac hypertrophy. IR promoted interactions between SH3GLB1 and mitochondrial membrane proteins, such as MFN1/2, TOM20 and Drp1, further indicating that the mechanism by which SH3GLB1 functions in cardiac hypertrophy might involve mitophagy. A bioinformatics prediction found that SUMO2 could SUMOylate SH3GLB1 at position K82. Consistent with this finding, both co-IP assays and laser confocal microscopy showed that IR promoted the interaction and colocalization of SUMO2 and SH3GLB1. In summary, our study identifies IR as an important factor that promotes hypertrophic cardiomyopathy by accelerating the activation of mitophagy through the SUMO2-mediated SUMOylation of SH3GLB1; thus, IR exerts dual therapeutic effects in the treatment of thoracic tumours with long-term radiotherapy. Additionally, this study provides novel treatment strategies and targets for preventing the hypertrophic cardiomyopathy caused by thoracic tumour radiotherapy. Furthermore, SH3GLB1 may be a promising experimental target for the development of strategies for treating cardiovascular diseases caused by IR.
肥厚型心肌病（HC）的特征是单个心肌细胞的增大，这是各种心血管疾病中发生的典型病理生理过程。电离辐射（IR）是肥厚型心肌病的一个重要独立危险因素，但潜在的分子机制尚不清楚。在本研究中，我们旨在阐明 IR 促进心脏肥大的作用，并研究 SUMO2 介导的 SH3GLB1 的 SUMO 化在 IR 诱导的心脏肥大中线粒体自噬中的作用机制。在体内，IR 通过激活线粒体自噬促进心脏肥大。在体外，IR 上调 PINK1 和 Parkin 蛋白表达并破坏线粒体形态结构。我们进一步证明，SH3GLB1 缺失抑制线粒体自噬的激活并恢复线粒体嵴，表明 SH3GLB1 在心脏肥大中具有调节作用。IR 促进 SH3GLB1 与线粒体膜蛋白（如 MFN1/2、TOM20 和 Drp1）之间的相互作用，进一步表明 SH3GLB1 在线粒体自噬中发挥作用的机制可能涉及线粒体自噬。生物信息学预测发现 SUMO2 可以在位置 K82 上 SUMO 化 SH3GLB1。与这一发现一致，共免疫沉淀测定和激光共聚焦显微镜显示，IR 促进 SUMO2 和 SH3GLB1 的相互作用和共定位。综上所述，我们的研究表明，IR 通过促进线粒体自噬的激活来促进肥厚型心肌病，这是通过 SH3GLB1 的 SUMO2 介导的 SUMO 化实现的；因此，IR 在治疗长期放疗的胸部肿瘤方面具有双重治疗效果。此外，该研究为预防胸部肿瘤放疗引起的肥厚型心肌病提供了新的治疗策略和靶点。此外，SH3GLB1 可能是开发治疗 IR 引起的心血管疾病的策略的有前途的实验靶标。
