Arabian Journal of Chemistry (Nov 2023)
Curcumin mediates macrophage polarization to inhibit the formation of abdominal aortic aneurysms by inhibiting the expression of histone acetyltransferase EP300
Abstract
Background: The onset of abdominal aortic aneurysm (AAA) is caused by local dilatation of the infrarenal abdominal aorta. Curcumin can affect the polarization and function of macrophage subsets in the context of vascular diseases. Curcumin, a natural EP300 inhibitor, may have therapeutic effects on vascular diseases. Objective: To explore the therapeutic pathway of curcumin in AAA. Methods: We found that the hub regulatory factor EP300 is the key factor by which curcumin acts on AAA through bioinformatics network pharmacology and molecular docking. We verified the localization of histone acetyltransferase EP300 in AAA tissue by immunohistochemistry (IHC) and immunofluorescence (IF) staining. Then, we used Real-time polymerase chain reaction (RT-PCR) to explore the high expression level of EP300 in human AAA tissues and analysed its correlation with key genes in AAA diseases. In addition, we successfully induced M1 macrophages and EP300 knockout macrophages with LPS/IFN-γ in vitro to investigate the effect of EP300 on macrophage polarization. Results: In our study, thirty important targets, including AKT1, STAT3, EGFR, EP300, GSK3B, APP, SERPINE1 and MMP14, were involved in the interaction between AAA and curcumin. Our molecular docking results showed that EP300 spontaneously binds to curcumin most easily. Therefore, we subsequently identified the histone acetyltransferase EP300 as the hub target of curcumin in AAA. IHC and IF staining of the outer membrane of AAA showed that EP300 was located in the mesa of AAA tissue, which was also the place where macrophages gathered. The mRNA expression of EP300 in human AAA tissue was upregulated, as shown by RT-PCR (P = 0.01). In in vitro RAW264.7 cells, we found that EP300 knockout in M0 macrophages significantly promoted the anti-inflammatory M2 polarization of macrophages and inhibited the proinflammatory M1 polarization of macrophages. Conclusion: Our research showed that in the therapeutic mechanism by which curcumin treats human AAA, histone acetyltransferase EP300 affected the progression of AAA by promoting aortic inflammation, acting on the immune environment, modulating macrophage proinflammatory polarization, and influencing the expression of other AAA target genes.
