Small ubiquitin-related modifier (SUMO)ylation of SIRT1 mediates (-)-epicatechin inhibited- differentiation of cardiac fibroblasts into myofibroblasts. (31st December 2022)

• Record Type: Journal Article
• Authors: Luo, Yingchun; Lu, Jing; Wang, Zeng; Wang, Lu; Wu, Guodong; Guo, Yuanyuan; Dong, Zengxiang
• Is Part Of: Pharmaceutical biology. Volume 60:Number 1(2022)
• Page Start: 1762
• Page End: 1770
• Publication Date: 2022-12-31
• Subjects: Flavanol -- cardiac fibrosis -- sirtuin -- SUMO1; Pharmacognosy -- Periodicals; Materia medica, Vegetable -- Periodicals; 615.321
• DOI: 10.1080/13880209.2022.2101672
• Languages: English
• ISSNs: 1388-0209

Abstract

Abstract: Context: (-)-Epicatechin (EPI) is a crucial substance involved in the protective effects of flavanol-rich foods. Previous studies have indicated EPI has a cardioprotective effect, but the molecular mechanisms in inhibition of cardiac fibrosis are unclear. Objective: We evaluated the effect of EPI in preventing cardiac fibrosis and the underlying molecular mechanism related to the SIRT1-SUMO1/AKT/GSK3β pathway. Materials and methods: Cardiac fibrosis mice model was established with transaortic constriction (TAC). Male C57BL/6 mice were randomly separated into 4 groups. Mice received 1 mg/kg/day of EPI or vehicle orally for 4 weeks. The acutely isolated cardiac fibroblasts were induced to myofibroblasts with 1 µM angiotensin II (Ang II). The cardiac function was measured with the ultrasonic instrument. Histological analysis of mice's hearts was determined with H&E or Masson method. The protein level of fibrosis markers, SUMOylation of SIRT1, and AKT/GSK3β pathway were quantified by immunofluorescence and western blot. Results: EPI treatment (1 mg/kg/day) could reverse the TAC-induced decline in LVEF (TAC, 61.28% ± 1.33% vs. TAC + EPI, 74.00% ± 1.64%), LVFS (TAC, 28.16% ± 0.89% vs. TAC + EPI, 37.18% ± 1.29%). Meantime, we found that 10 µM EPI blocks Ang II-induced transformation of cardiac fibroblasts into myofibroblasts. The underlying mechanism of EPI-inhibited myofibroblasts transformation involves activation of SUMOylation of SIRT1 through SP1. Furthermore, SUMOylation of SIRT1 inhibited Ang II-induced fibrogenic effect via the AKT/GSK3β pathway. Conclusion: EPI plays a protective effect on cardiac fibrosis by regulating the SUMO1-dependent modulation of SIRT1, which provides a theoretical basis for use in clinical therapies.