Wei Tianwen, Du Yingqiang, Shan Tiankai, Chen Jiawen, Shi Dongwei, Yang Tongtong, Wang Jiankang, Zhang Jun, Li Yafei
Department of Cardiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu Province, China.
Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
Bioengineered. 2022 Apr;13(4):8836-8849. doi: 10.1080/21655979.2022.2054913.
Myocardial fibrosis, a common pathological manifestation of cardiac remodeling (CR), often leads to heart failure (HF) and even death. The underlying molecular mechanism of the role of TRIM33 in Ang II-induced myocardial fibrosis is not fully understood. We found that TRIM33 was specifically upregulated in CFs and myocardial tissue after Ang II stimulation. Adult mice induced by Ang II were used as models, and Ang II-induced neonatal mouse primary cardiac fibroblasts (CFs) were used as models. The level of CF fibrosis was assessed by CF proliferation, migration, activation and extracellular matrix (ECM) synthesis. In addition, Masson staining, the heart weight/body weight (HW/BW) ratio and echocardiography were used to evaluate the effect of TRIM33. TRIM33 expression was specifically upregulated in CFs and myocardial tissue after Ang II stimulation. In experiments, we found that TRIM33 knockdown promoted Ang II-induced CF proliferation, while TRIM33 overexpression weakened Ang II-induced CF proliferation, migration, activation and collagen synthesis. Mechanistically, we showed that TRIM33, negatively regulated by HSPB5, mediated its antifibrotic effect by inhibiting the activation of TGF-β1 and its downstream genes, Smad3 and Smad4. Finally, TRIM33 overexpression suppressed fibrosis and promoted cardiac repair and functional recovery in Ang II-induced mice. Our results clearly establish that TRIM33 limits cardiac fibrosis by hindering CF proliferation, migration, activation and collagen synthesis. Enhancing these beneficial functions of TRIM33 by a targeting vector might be a novel therapeutic strategy for CR.
心肌纤维化是心脏重塑（CR）的常见病理表现，常导致心力衰竭（HF）甚至死亡。TRIM33在血管紧张素II诱导的心肌纤维化中作用的潜在分子机制尚未完全明确。我们发现，血管紧张素II刺激后，TRIM33在成纤维细胞（CFs）和心肌组织中特异性上调。使用血管紧张素II诱导的成年小鼠作为模型，以及血管紧张素II诱导的新生小鼠原代心脏成纤维细胞（CFs）作为模型。通过CF增殖、迁移、活化和细胞外基质（ECM）合成来评估CF纤维化水平。此外，采用Masson染色、心脏重量/体重（HW/BW）比值和超声心动图来评估TRIM33的作用效果。血管紧张素II刺激后，TRIM33表达在CFs和心肌组织中特异性上调。在实验中，我们发现敲低TRIM33促进血管紧张素II诱导的CF增殖，而过表达TRIM33则减弱血管紧张素II诱导的CF增殖、迁移、活化和胶原蛋白合成。机制上，我们表明TRIM33受HSPB5负调控，通过抑制TGF-β1及其下游基因Smad3和Smad4的活化来介导其抗纤维化作用。最后，过表达TRIM33可抑制血管紧张素II诱导的小鼠纤维化，并促进心脏修复和功能恢复。我们的结果清楚地表明，TRIM33通过阻碍CF增殖、迁移、活化和胶原蛋白合成来限制心脏纤维化。通过靶向载体增强TRIM33的这些有益功能可能是CR的一种新型治疗策略。
