ABSTRACT
Disturbance of macrophage-associated lipid metabolism plays a key role in atherosclerosis. Crosstalk between autophagy deficiency and inflammation response in foam cells (FCs) through epigenetic regulation is still poorly understood. Here, we demonstrate that in macrophages, oxidized low-density lipoprotein (ox-LDL) leads to abnormal crosstalk between autophagy and inflammation, thereby causing aberrant lipid metabolism mediated through a dysfunctional transcription factor EB (TFEB)-P300-bromodomain-containing protein 4 (BRD4) axis. ox-LDL led to macrophage autophagy deficiency along with TFEB cytoplasmic accumulation and increased reactive oxygen species generation. This activated P300 promoted BRD4 binding on the promoter regions of inflammatory genes, consequently contributing to inflammation with atherogenesis. Particularly, ox-LDL activated BRD4-dependent super-enhancer associated with liquid-liquid phase separation (LLPS) on the regulatory regions of inflammatory genes. Curcumin (Cur) prominently restored FCs autophagy by promoting TFEB nuclear translocation, optimizing lipid catabolism, and reducing inflammation. The consequences of P300 and BRD4 on super-enhancer formation and inflammatory response in FCs could be prevented by Cur. Furthermore, the anti-atherogenesis effect of Cur was inhibited by macrophage-specific Brd4 overexpression or Tfeb knock-out in Apoe knock-out mice via bone marrow transplantation. The findings identify a novel TFEB-P300-BRD4 axis and establish a new epigenetic paradigm by which Cur regulates autophagy, inhibits inflammation, and decreases lipid content.
ABSTRACT
Objective@#To investigate the correlation of single nucleotide polymorphisms (SNPs) in autophage-related 5 ( ATG5 ) gene promoter with acute myocardial infarction (AMI). @*Methods@#The SNPs of ATG5 gene promoter were detected by polymerase chain reaction (PCR) and Sanger sequencing. The typing and correlation of SNPs in 378 AMI patients and 374 healthy controls were analyzed by Chi-square test, Logistic regression analysis and haplotype analysis. @*Results@#Two SNPs of ATG5 gene promoter, rs506027 (OR=1.4, 95% CI \[0.6-3.0\], P=0.411) and rs510432 (OR=1.6, 95% CI \[0.7-3.4\], P=0.275), were found. They didn′t increase the susceptibility of AMI, and the haplotype associated with AMI was not found in the two SNPs. @*Conclusion@#The polymorphism of ATG5 gene promoter isn′t associated with the susceptibility of AMI.