BACH2 ameliorates cell apoptosis and autophagy as a molecular switch of BCL-2/Beclin-1 complex in myocardial infarction.

Abstract

Myocardial infarction is a major cause of death and disability worldwide. Programmed cell death (PCD) of cardiomyocytes is a predominant pathological manifestation. However, the specific PCD subtypes involved in myocardial infarction remain largely elusive, and detailed therapeutic strategies require further exploration. Various forms of PCD were detected in myocardial infarction models in vivo and in vitro. The expression and cellular localization of the transcriptional factor BACH2 were monitored using western blot, qRT-PCR, immunofluorescent staining, and isolation of nuclear and cytoplasmic proteins in a time- and dose-dependent manner. Cardiac-specific knockout/knockin mice were genetically established by crossing BACH2flox/flox mice / BACH2 Rosa26flox/flox mice with MYH6-Cre mice, followed by Tamoxifen injection. RNA-seq analysis combined with CUT&Tag assays were performed to identify underlying molecular targets. Immunoprecipitation, chromatin immunoprecipitation, site-specific mutation, dual luciferase activity assays, and specific antagonists were used for mechanism studies. A BACH2 agonist was identified and injected into wild-type and BACH2 conditional knockout mice with myocardial infarction to assess its clinical potential. Apoptosis and autophagy are the two dominant PCD subtypes in myocardial infarction. BACH2 translocated from the nucleus to the cytoplasm upon hypoxia/ reoxygenation (H/R) stimulation, and its total protein levels decreased. Cardiac knockout of BACH2 aggravated, while knockin of BACH2 ameliorated cardiac dysfunction caused by myocardial infarction in both mouse models and cultured cells. Mechanistically, BACH2 bound to a specific site on the promoter of BCL2. On one hand, BACH2 increased the mRNA levels of BCL2, leading to the suppression of cardiomyocyte apoptosis; on the other hand, BACH2 enhanced the formation of the BCL2/Beclin-1 complex, resulting in the inhibition of autophagy. The natural small compound Myricetin was identified as an efficient activator of BACH2 and protected the heart from myocardial infarction in a BACH2-dependent manner. Cardiomyocyte apoptosis and autophagy are the predominant forms of PCD in this context. BACH2 functions as a molecular switch by transcriptionally promoting BCL2 expression and the formation of the BCL2/Beclin-1 complex, thereby inhibiting both cardiomyocyte apoptosis and autophagy during myocardial infarction. Small molecules targeting BACH2 may represent a promising therapeutic strategy for patients with myocardial infarction.