Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024 Sept 28;49(9):1390-1399. doi: 10.11817/j.issn.1672-7347.2024.230335.
ABSTRACT
OBJECTIVES: Cardiac remodeling is a critical pathological process leading to heart failure. Currently, there is a lack of specific and effective therapies targeting pathological cardiac remodeling. Epigenetics has been shown to play a regulatory role in pathological remodeling. This study aims to explore the impact of inhibiting histone methyltransferase enhancer of zeste homolog 2 (EZH2)-mediated abnormal histone 3 lysine 27 trimethylation (H3K27me3) methylation modification on the progression of pressure overload-induced cardiac remodeling in mice.
METHODS: Male Kunming mice (specific pathogen-free grade) were randomly divided into groups for 2 experimental parts. Thoracic aortic constriction (TAC) surgery was performed to establish a mouse model of pressure overload-induced cardiac remodeling. In part 1, mice were divided into Normal, Sham, TAC-4W (TAC 4 weeks post-surgery), and TAC-8W (TAC 8 weeks post-surgery) groups. In part 2, mice were divided into Normal, Sham, TAC-8W, TAC+Vehicle (Veh) (TAC with distilled water gavage), and TAC+tanshinone I (Tan I) (TAC with Tan I gavage) groups. Cardiac structure and function were assessed using echocardiography. Histological analysis, Western blotting, and wheat germ agglutinin (WGA) staining was used to evaluate myocardial tissue and cellular changes.
RESULTS: Gross examination revealed that the hearts of mice in the TAC-8W group were larger than those in the Sham group, and the hearts in the TAC+Tan I group were further enlarged compared to the TAC-8W group. Echocardiographic analysis showed that, compared to the Sham group, mice in the TAC-4W group exhibited significantly increased left ventricular anterior wall thickness (LVAWT), left ventricular posterior wall thickness (LVPWT), and left ventricular ejection fraction (LVEF), while left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) were significantly decreased (all P<0.05). Compared to the TAC-4W group, the TAC-8W displayed LVAWT, LVPWT, and LVEF, along with increased LVEDD, LVESD, and left ventricular volume (LVV) (all P<0.05). Furthermore, compared to the TAC-8W group, the TAC+Tan I group demonstrated further reductions in decreased EZH2 and H3K27me3 expression and increased LVAWT, LVPWT, and LVEF, while LVEDD, LVESD, and LVV increased significantly (all P<0.05). Western blotting analysis showed that, compared to the Sham group, the expression levels of EZH2 and H3K27me3 in myocardial tissue were significantly reduced in the TAC-4W and TAC-8W groups, whereas β-MHC expression was significantly increased (all P<0.05). Compared to the TAC-8W group, the TAC+Tan I group exhibited further reductions in EZH2 and H3K27me3 expression levels, along with a significant increase in β-MHC expression (all P<0.05). WGA staining results showed that cardiomyocyte area in the TAC-8W group was significantly larger than that in the Sham group (P<0.05). Compared to the TAC-8W group, the TAC+Tan I group displayed an even greater increase in cardiomyocyte area (P<0.05). Additionally, the number of cardiomyocytes per unit area was significantly lower in the TAC-8W group compared to the Sham group (P<0.05), and this reduction was further exacerbated in the TAC+Tan I group compared to the TAC-8W group (P<0.05).
CONCLUSIONS: EZH2 inhibition-mediated reduction in H3K27me3 methylation promotes pressure overload-induced cardiac remodeling in mice. EZH2 may serve as a novel therapeutic target for the prevention and treatment of pathological cardiac remodeling.
PMID:39931769 | DOI:10.11817/j.issn.1672-7347.2024.230335
