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

作者：Yan Zhang, Yang Cao, Rui Zheng, Zhenyu Xiong, Zhengru Zhu, Fanya Gao, Wanrong Man, Yu Duan, Jie Lin, Xuebin Zhang, Dexi Wu, Mengyuan Jiang, Xiao Zhang, Congye Li, Xiaoming Gu, Yanhong Fan, Dongdong Sun · 发表于：Theranostics · 年份：2022 · DOI：10.7150/thno.77043 · 被引用次数：49 · 研究领域：Cardiac Fibrosis and Remodeling、Tissue Engineering and Regenerative Medicine、Cardiovascular Function and Risk Factors

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.Furthe...