Theranostics 2021; 11(3):1249-1268. doi:10.7150/thno.48787 This issue Cite

Research Paper

Low-density lipoprotein receptor-related protein 6 regulates cardiomyocyte-derived paracrine signaling to ameliorate cardiac fibrosis

Xiang Wang1#, Yan Zou1#, Zhidan Chen1#, Yang Li1#, Le Pan1, Ying Wang1, Ming Liu1, Chao Yin1, Jian Wu1, Chunjie Yang1, Lei Zhang1, Chenze Li2, Zheyong Huang1, Daowen Wang2, Juying Qian1, Junbo Ge1, Yunzeng Zou1✉, Hui Gong1✉

1. Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
2. Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
#These authors contributed equally to this work.

Citation:
Wang X, Zou Y, Chen Z, Li Y, Pan L, Wang Y, Liu M, Yin C, Wu J, Yang C, Zhang L, Li C, Huang Z, Wang D, Qian J, Ge J, Zou Y, Gong H. Low-density lipoprotein receptor-related protein 6 regulates cardiomyocyte-derived paracrine signaling to ameliorate cardiac fibrosis. Theranostics 2021; 11(3):1249-1268. doi:10.7150/thno.48787. https://www.thno.org/v11p1249.htm
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Abstract

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Rationale: Maladaptive cardiac remodeling is a critical step in the progression of heart failure. Low-density lipoprotein receptor-related protein 6 (LRP6), a co-receptor of Wnt, has been implicated in cardiac protection. We aimed to study the role of cardiomyocyte-expressed LRP6 in cardiac remodeling under chronic pressure overload.

Methods: Cardiac parameters were analyzed in inducible cardiac-specific LRP6 overexpressing and control mice subjected to transverse aortic constriction (TAC).

Results: Cardiac LRP6 was increased at an early phase after TAC. Cardiomyocyte-specific LRP6 overexpression improved cardiac function and inhibited cardiac hypertrophy and fibrosis four weeks after TAC. The overexpression significantly inhibited β-catenin activation, likely contributing to the inhibitory effect on cardiac hypertrophy after TAC. LRP6 overexpression reduced the expression and secretion of Wnt5a and Wnt11 by cardiomyocytes, and knockdown of Wnt5a and Wnt11 greatly inhibited cardiac fibrosis and dysfunction under pressure overload in vitro and in vivo. Cardiomyocyte-expressed LRP6 interacted with cathepsin D (CTSD, a protease) and promoted the degradation of Wnt5a and Wnt11, inhibiting cardiac fibrosis and dysfunction induced by TAC. The protease inhibitor leupeptin attenuated the interaction between LRP6 and CTSD, enhanced the expression of Wnt5a and Wnt11, and deteriorated cardiac function and fibrosis in cardiomyocyte-specific LRP6-overexpressing mice under pressure overload. Mutants from human patients, P1427Q of LRP6 and G316R of CTSD significantly inhibited the interaction between LRP6 and CTSD and increased Wnt5a and Wnt11 expression.

Conclusion: Cardiomyocyte-expressed LRP6 promoted the degradation of Wnt5a and Wnt11 by regulating CTSD and inhibited cardiac fibrosis under pressure overload. Our study demonstrated a novel role of LRP6 as an anti-fibrosis regulator.

Keywords: Pressure overload, Cardiac fibrosis, LRP6, Wnt5a, Wnt11, CTSD


Citation styles

APA
Wang, X., Zou, Y., Chen, Z., Li, Y., Pan, L., Wang, Y., Liu, M., Yin, C., Wu, J., Yang, C., Zhang, L., Li, C., Huang, Z., Wang, D., Qian, J., Ge, J., Zou, Y., Gong, H. (2021). Low-density lipoprotein receptor-related protein 6 regulates cardiomyocyte-derived paracrine signaling to ameliorate cardiac fibrosis. Theranostics, 11(3), 1249-1268. https://doi.org/10.7150/thno.48787.

ACS
Wang, X.; Zou, Y.; Chen, Z.; Li, Y.; Pan, L.; Wang, Y.; Liu, M.; Yin, C.; Wu, J.; Yang, C.; Zhang, L.; Li, C.; Huang, Z.; Wang, D.; Qian, J.; Ge, J.; Zou, Y.; Gong, H. Low-density lipoprotein receptor-related protein 6 regulates cardiomyocyte-derived paracrine signaling to ameliorate cardiac fibrosis. Theranostics 2021, 11 (3), 1249-1268. DOI: 10.7150/thno.48787.

NLM
Wang X, Zou Y, Chen Z, Li Y, Pan L, Wang Y, Liu M, Yin C, Wu J, Yang C, Zhang L, Li C, Huang Z, Wang D, Qian J, Ge J, Zou Y, Gong H. Low-density lipoprotein receptor-related protein 6 regulates cardiomyocyte-derived paracrine signaling to ameliorate cardiac fibrosis. Theranostics 2021; 11(3):1249-1268. doi:10.7150/thno.48787. https://www.thno.org/v11p1249.htm

CSE
Wang X, Zou Y, Chen Z, Li Y, Pan L, Wang Y, Liu M, Yin C, Wu J, Yang C, Zhang L, Li C, Huang Z, Wang D, Qian J, Ge J, Zou Y, Gong H. 2021. Low-density lipoprotein receptor-related protein 6 regulates cardiomyocyte-derived paracrine signaling to ameliorate cardiac fibrosis. Theranostics. 11(3):1249-1268.

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