Berberine Inhibited SASP-Related Inflammation through RXRα/PPARγ/NEDD4 Pathway in Atherosclerosis

The accumulation of aging cells significantly contributes to chronic inflammatory diseases such as atherosclerosis. Human carotid artery single-cell Sequencing has shown that large numbers of aging foam cells are present in the plaques of human patients. Berberine (BBR) has been shown to inhibit cell senescence, however, the mechanisms involved in its treatment of atherosclerotic senescence have not yet been determined. Changes in plaque morphology and blood chemistry were observed in apoE[Formula: see text] mice fed with a high-fat diet before and after BBR treatment. Inflammatory proteins linked to the senescence-associated secretory phenotypes (SASP) were detected in RAW264.7 and peritoneal macrophage-derived foam cells. Smart-seq analysis was used to explore the pathways associated with BBR therapy for atherosclerosis. Finally, the effect of lentivirus-mediated knockdown of RXRα in macrophages in plaques on atherosclerosis treatment with BBR was determined. We found that BBR reduced inflammation linked to SASP in atherosclerosis through the RXRα/PPARγ/NEDD4 signaling pathway. BBR increased GATA4 binding to p62, promoted ubiquitination, and inhibited SASP-associated protein production in RAW264.7 and peritoneal macrophage-derived foam cells. Mechanistically, according to the Smart-seq results, BBR activated RXRα and PPARγ, synergistically increased NEDD4 transcription levels, and promoted ubiquitination-mediated degradation of the GATA4/p62 complex. Additionally, the Anti-aging impact of BBR on atherosclerosis was negated when macrophage-specific RXRα was knocked down using lentivirus (pLVCD68-shRNA RXRα) in apoE[Formula: see text] mice. BBR activated PPARγ through RXRα-PPARγ immune complex in macrophage-derived foam cells, increased NEDD4 transcriptional activity, promoted ubiquitination of GATA4-p62 complex, and inhibited SASP-related inflammation. These findings suggest the potential of BBR as a novel approach to addressing SASP-associated inflammation in atherosclerosis.

Atherosclerosis; Berberine; Inflammation; RXRα/PPARγ/NEDD4; SASP.