Int J Biol Sci 2023; 19(1):137-155. doi:10.7150/ijbs.77469 This issue Cite

Research Paper

N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation

Mingchuan Liu1#, Tingwei Peng1#, Lang Hu1#, Min Wang2, Dong Guo1, Bingchao Qi1, Gaotong Ren1, Di Wang1, Yunqing Li3, Liqiang Song2, Jianqiang Hu1✉, Yan Li1✉

1. Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
2. Department of Pulmonary and Critical Care Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
3. Brigade 2, College of Basic Medicine, The Fourth Military Medical University, Xi'an, 710038, China.
#These authors contributed equally to this work.

Citation:
Liu M, Peng T, Hu L, Wang M, Guo D, Qi B, Ren G, Wang D, Li Y, Song L, Hu J, Li Y. N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation. Int J Biol Sci 2023; 19(1):137-155. doi:10.7150/ijbs.77469. https://www.ijbs.com/v19p0137.htm
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Abstract

Graphic abstract

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.

Keywords: CD147, diabetic cardiomyopathy, cardiac fibrosis, ALK5


Citation styles

APA
Liu, M., Peng, T., Hu, L., Wang, M., Guo, D., Qi, B., Ren, G., Wang, D., Li, Y., Song, L., Hu, J., Li, Y. (2023). N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation. International Journal of Biological Sciences, 19(1), 137-155. https://doi.org/10.7150/ijbs.77469.

ACS
Liu, M.; Peng, T.; Hu, L.; Wang, M.; Guo, D.; Qi, B.; Ren, G.; Wang, D.; Li, Y.; Song, L.; Hu, J.; Li, Y. N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation. Int. J. Biol. Sci. 2023, 19 (1), 137-155. DOI: 10.7150/ijbs.77469.

NLM
Liu M, Peng T, Hu L, Wang M, Guo D, Qi B, Ren G, Wang D, Li Y, Song L, Hu J, Li Y. N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation. Int J Biol Sci 2023; 19(1):137-155. doi:10.7150/ijbs.77469. https://www.ijbs.com/v19p0137.htm

CSE
Liu M, Peng T, Hu L, Wang M, Guo D, Qi B, Ren G, Wang D, Li Y, Song L, Hu J, Li Y. 2023. N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation. Int J Biol Sci. 19(1):137-155.

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