[Role of RhoE gene expression changes in myocardial fibrosis in diabetic cardiomyopathy].

<b>Objective:</b> To explore the role and mechanism of Ras homolog gene family member E (RhoE) gene in myocardial fibrosis in diabetic cardiomyopathy. <b>Methods:</b> Wild-type SD rats were intraperitoneally injected with streptozotocin solution (STZ, 70 mg/kg) and an equal volume of sodium citrate solution to establish the type 1 diabetes mellitus (T1DM) group (<i>n</i>=15) and the T1DM control group (<i>n</i>=15), respectively. db/db spontaneous type 2 diabetes mellitus (T2DM) mice and wild-type C57BL/6J mice were conventionally housed for 8 weeks to establish the T2DM group (<i>n</i>=5) and the T2DM control group (<i>n</i>=5), respectively. Heterozygote SD rats with systemic knockout of the RhoE gene were intraperitoneally injected with STZ solution (70 mg/kg) and an equal volume of sodium citrate solution to establish the RhoE knockout T1DM group (<i>n</i>=5) and the RhoE knockout control group (<i>n</i>=5), respectively. Wild-type SD rats were injected with RhoE-overexpressing adeno-associated virus 9 through tail vein and intraperitoneally injected with STZ solution (70 mg/kg) to establish the RhoE overexpression T1DM group (<i>n</i>=5), while wild-type SD rats injected with negative control virus through tail vein and intraperitoneally injected with an equal volume of sodium citrate solution served as the RhoE overexpression control group (<i>n</i>=5). After successful modeling, all animals in each group were conventionally housed for an additional 6 or 8 weeks, which marked the experimental endpoint. At the experimental endpoint, echocardiography was performed to assess cardiac function of animals in each group, and left ventricular ejection fraction (LVEF) and the ratio of early to late diastolic transmitral flow velocity (E/A ratio) were analysed. Masson staining was used to detect collagen fiber deposition in myocardial tissue of animals in each group. Western blot analysis was conducted to detect the expression levels of RhoE gene, type Ⅰ collagen, type Ⅲ collagen, Smad2/3, and phosphorylated Smad2/3 protein in myocardial tissue of rats. Enzyme-linked immunosorbent assay was used to measure the levels of transforming growth factor-β1 (TGF-β1) in serum of rats. <b>Results:</b> Compared with their respective control groups, the expression of RhoE in the heart tissues of mice in the T2DM group and rats in the T1DM group was significantly downregulated, and the deposition of collagen fibers was more significant (<i>P</i><0.05), and LVEF and E/A ratio were lower (all <i>P</i><0.05). Compared with the T1DM group, the phosphorylation level of Smad2/3、the levels of type Ⅰ collagen and type Ⅲ collagen in myocardial tissue and the level of TGF-β1 in serum were higher in the RhoE knockout T1DM group (all <i>P</i><0.05). Additionally, rats in the RhoE overexpression T1DM group had higher LVEF and E/A ratios (both <i>P</i><0.05) and less collagen fiber deposition (<i>P</i><0.05) compared with the T1DM group. <b>Conclusions:</b> Myocardial fibrosis induced by diabetes mellitus activates TGF-β1/Smads signaling pathway by inhibiting RhoE gene expression. Myocardial targeting overexpression of the RhoE mediated by adeno-associated virus 9 can alleviate myocardial fibrosis and improve cardiac function in rats with diabetic cardiomyopathy.