Theranostics 2022; 12(17):7250-7266. doi:10.7150/thno.77043 This issue Cite

Research Paper

Fibroblast-specific activation of Rnd3 protects against cardiac remodeling in diabetic cardiomyopathy via suppression of Notch and TGF-β signaling

Yan Zhang1*, Yang Cao1*, Rui Zheng2*, Zhenyu Xiong1, Zhengru Zhu3, Fanya Gao4, Wanrong Man1, Yu Duan1, Jie Lin1, Xuebin Zhang1, Dexi Wu1, Mengyuan Jiang1, Xiao Zhang1, Congye Li1, Xiaoming Gu5, Yanhong Fan1✉, Dongdong Sun1✉

1. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
2. Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
3. Department of Otolaryngology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
4. Department of General Practice, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
5. Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.
*These authors contributed equally to this work.

Citation:
Zhang Y, Cao Y, Zheng R, Xiong Z, Zhu Z, Gao F, Man W, Duan Y, Lin J, Zhang X, Wu D, Jiang M, Zhang X, Li C, Gu X, Fan Y, Sun D. Fibroblast-specific activation of Rnd3 protects against cardiac remodeling in diabetic cardiomyopathy via suppression of Notch and TGF-β signaling. Theranostics 2022; 12(17):7250-7266. doi:10.7150/thno.77043. https://www.thno.org/v12p7250.htm
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Abstract

Graphic abstract

Rationale: Extracellular matrix (ECM) remodeling, a key pathological feature in diabetic cardiomyopathy (DCM), is triggered by oxidative stress, inflammation, and various metabolic disorders in the heart. Cardiac fibroblasts (CFs) are the primary source of ECM proteins and the ultimate effector cells in ECM remodeling. CFs are turned on and differentiated into myofibroblasts in response to profibrotic signaling. Rnd3 is a small Rho-GTPase involved in the regulation of cell-cycle distribution, cell migration, and cell morphogenesis. Emerging evidence suggests a link between Rnd3 expression and onset of cardiovascular diseases. However, the role of Rnd3 in DCM remains unknown.

Methods: Flow cytometry was employed to separate different types of cardiac cells. Type 2 diabetes mellitus was established in Rnd3 fibroblast-specific knockout and transgenic mice. RNA sequencing and chromatin immunoprecipitation assay were used to discern signaling pathways involved.

Results: Rnd3 expression was reduced in cardiac tissues of diabetic mice, with CFs being the primary cell type. Fibroblast-specific upregulation of Rnd3 in vivo was protective against DCM, whereas Rnd3 downregulation in fibroblasts accentuated cardiac oxidative stress, fibrosis, ventricular remodeling, and dysfunction. Moreover, in vitro Rnd3 overexpression significantly attenuated reactive oxygen species production, CF migration and proliferation under high levels of glucose (35 mmol/L) and palmitic acid (500 µmol/L) challenge. Furthermore, RNA sequencing indicated that Notch and TGF-β signaling were significantly suppressed upon Rnd3 overexpression. Mechanistically, Rnd3 regulated Notch and TGF-β signaling by interacting with NICD and ROCK1, respectively. Specifically, glucotoxicity and lipotoxicity control Rnd3 expression by regulating the binding of Nr1H2 and Rnd3 promoter.

Conclusions: Our findings provide compelling evidence in that fibroblast-specific activation of Rnd3 protects against cardiac remodeling in DCM, indicating promises of targeting Rnd3 in the treatment of DCM.

Keywords: Cardiac remodeling, Cardiac fibrosis, Rho-GTPase, Cardiac fibroblast, Oxidative stress


Citation styles

APA
Zhang, Y., Cao, Y., Zheng, R., Xiong, Z., Zhu, Z., Gao, F., Man, W., Duan, Y., Lin, J., Zhang, X., Wu, D., Jiang, M., Zhang, X., Li, C., Gu, X., Fan, Y., Sun, D. (2022). Fibroblast-specific activation of Rnd3 protects against cardiac remodeling in diabetic cardiomyopathy via suppression of Notch and TGF-β signaling. Theranostics, 12(17), 7250-7266. https://doi.org/10.7150/thno.77043.

ACS
Zhang, Y.; Cao, Y.; Zheng, R.; Xiong, Z.; Zhu, Z.; Gao, F.; Man, W.; Duan, Y.; Lin, J.; Zhang, X.; Wu, D.; Jiang, M.; Zhang, X.; Li, C.; Gu, X.; Fan, Y.; Sun, D. Fibroblast-specific activation of Rnd3 protects against cardiac remodeling in diabetic cardiomyopathy via suppression of Notch and TGF-β signaling. Theranostics 2022, 12 (17), 7250-7266. DOI: 10.7150/thno.77043.

NLM
Zhang Y, Cao Y, Zheng R, Xiong Z, Zhu Z, Gao F, Man W, Duan Y, Lin J, Zhang X, Wu D, Jiang M, Zhang X, Li C, Gu X, Fan Y, Sun D. Fibroblast-specific activation of Rnd3 protects against cardiac remodeling in diabetic cardiomyopathy via suppression of Notch and TGF-β signaling. Theranostics 2022; 12(17):7250-7266. doi:10.7150/thno.77043. https://www.thno.org/v12p7250.htm

CSE
Zhang Y, Cao Y, Zheng R, Xiong Z, Zhu Z, Gao F, Man W, Duan Y, Lin J, Zhang X, Wu D, Jiang M, Zhang X, Li C, Gu X, Fan Y, Sun D. 2022. Fibroblast-specific activation of Rnd3 protects against cardiac remodeling in diabetic cardiomyopathy via suppression of Notch and TGF-β signaling. Theranostics. 12(17):7250-7266.

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