EGCG protected against myocardial I/RI by modulating Gm4419/DUSP5/ERK1/2-mediated autophagy. - GreenMedInfo Summary
EGCG protects against myocardial I/RI by regulating lncRNA Gm4419-mediated epigenetic silencing of the DUSP5/ERK1/2 axis.
Toxicol Appl Pharmacol. 2021 Nov 2 ;433:115782. Epub 2021 Nov 2. PMID: 34740634
Min Zeng
BACKGROUND: Epigallocatechin gallate (EGCG) has attracted increasing attention due to its beneficial effect on cardiovascular health. The aim of this study was to investigate the underlying mechanism by which EGCG protects against myocardial ischaemia/reperfusion injury (I/RI).
METHODS: Murine myocardial I/RI and HO-induced cardiomyocyte injury models were established to evaluate the therapeutic effects of EGCG. In the myocardial I/RI mouse model, the echocardiographic parameters of ejection fraction (EF) and fraction shortening (FS) levels, infarct size, histological evaluation and transmission electron microscopy (TEM) were used to evaluate cardiac tissue damage and autophagy. MTT assays, TUNEL staining, flow cytometry and immunofluorescence (IF) were used to monitor cell viability, apoptosis and autophagy in vitro. qRT-PCR and western blotting were used to determine the mRNA and protein levels of key molecules, respectively. The epigenetic regulation of DUSP5 was assessed via RNA immunoprecipitation (RIP), RNA pull-down and chromatin immunoprecipitation (ChIP) assays.
RESULTS: EGCG significantly improved cardiac function, reduced infarct size, enhanced cell viability and inhibited autophagic activity in both myocardial I/RI mouse models and HO-induced cardiomyocyte injury models. Moreover, EGCG suppressed HO- or myocardial I/R-increased Gm4419 expression, and Gm4419 overexpression dramatically abolished EGCG-mediated protective effects against myocardial I/RI. Mechanistically, Gm4419 epigenetically suppressed DUSP5 by recruiting EZH2, thus activating ERK1/2 pathway-mediated autophagy. Furthermore, the in vivo experiments further verified that the Gm4419-mediated disruptive effects of EGCG on myocardial I/RI were potentiated by DUSP5 knockdown but attenuated by DUSP5 overexpression.
CONCLUSIONS: In conclusion, our findings demonstrated that EGCG protected against myocardial I/RI by modulating Gm4419/DUSP5/ERK1/2-mediated autophagy.
