N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation.
N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation.
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DOI：
10.7150/ijbs.77469
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发表时间：
2023
影响因子：
9.2
通讯作者：
Li, Yan
中科院分区：
文献类型：
--
作者：
Liu, Mingchuan;Peng, Tingwei;Hu, Lang;Wang, Min;Guo, Dong;Qi, Bingchao;Ren, Gaotong;Wang, Di;Li, Yunqing;Song, Liqiang;Hu, Jianqiang;Li, Yan
纤维化在糖尿病心肌病（DCM）中的重要作用已被越来越多的研究所证实，但其发病机制尚不清楚。考虑到分化抗原147（Cluster of Differentiation 147，CD 147）在纤维化疾病的发病机制中的独特和重叠作用，本研究旨在探讨CD 147在扩张型心肌病纤维化中的作用及其机制。AAV 9介导的心脏特异性CD 147沉默减轻糖尿病小鼠的心脏纤维化和心脏功能CD 147基因敲低显著抑制高糖诱导的CFs活化。在机制上，CD 147直接与I型转录生长因子β（TGF-β）受体I（ALK 5）结合，促进ALK 5活化和内吞作用，以诱导SMAD 2/3磷酸化和核转位。此外，HG通过促进GNT-V介导的N-糖基化来阻止泛素-蛋白酶体依赖的CD 147降解。结果，对照小鼠心脏特异性CD 147过表达模拟糖尿病诱导的心脏纤维化，加重心脏功能。重要的是，与非糖尿病患者相比，糖尿病患者的血清和心肌标本中CD 147也上调，伴有心功能不全和过度胶原沉积的超声心动图指标。我们的研究提供了第一个证据表明，CD 147作为一个关键因素，促进糖尿病心脏纤维化，并可能有助于未来的发展CD 147为基础的治疗策略DCM。
Emerging evidence has implicated the important role of fibrosis in diabetic cardiomyopathy (DCM), while the underlying mechanism remains unclear. Considering the distinct and overlapping roles of Cluster of Differentiation 147 (CD147) in the pathogenesis of fibrotic diseases, we aim to investigate the role of CD147 in the fibrosis of DCM and explore its underlying mechanism. AAV9-mediated cardiac-specific CD147 silencing attenuated cardiac fibrosis and cardiac function in diabetic mice. CD147 knockdown significantly inhibited high glucose (HG)-induced activation of CFs. Mechanistically, CD147 directly bound to type I transcription growth factor β (TGF-β) receptor I (ALK5), promoting ALK5 activation and endocytosis to induce SMAD2/3 phosphorylation and nuclear translocation. In addition, HG prevented the ubiquitin-proteasome-dependent degradation of CD147 by promoting GNT-V-mediated N-glycosylation. As a result, cardiac-specific CD147 overexpression in control mice mimicked diabetes-induced cardiac fibrosis, aggravating cardiac function. Importantly, CD147 was also upregulated in serum and myocardial specimens from patients with diabetes compared with non-diabetes, accompanied by echocardiographic indices of cardiac dysfunction and excessive collagen deposition. Our study provides the first evidence that CD147 acts as a pivotal factor to promote diabetic cardiac fibrosis, and may contribute to the development of future CD147-based therapeutic strategies for DCM.
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