Anti-atherogenic actions of pomegranate polyphenol punicalagin and Its metabolites: In vitro Effects on vascular cells and in vivo atheroprotection by urolithin A via anti-inflammatory and plaque-stabilising mechanisms

Notably, some metabolite-specific effects were observed, such as increased ROS production by urolithin B in various cell types. Given its broad inhibitory effects on pro-atherogenic processes, urolithin A (UA) was further evaluated in vivo using LDL receptor-deficient mice fed a high-fat diet. UA supplementation led to reduced circulating levels of natural killer cells, granulocytes, and macrophages, alongside elevated levels of gut microbiota-derived short-chain fatty acids in plasma and faeces.

Histological and immunohistological analysis showed that UA significantly reduced plaque content and inflammation, as evidenced by decreased macrophage and T-cell infiltration, and increased markers of plaque stability, including smooth muscle cell and collagen content. RNA sequencing of the thoracic aorta, followed by bioinformatic analysis, identified key genes and pathways involved in the anti-inflammatory and anti-atherogenic actions of UA.

These findings provide novel insights into the therapeutic potential of PC and its metabolites particularly UA and support further investigation in human clinical trials.