Punicalin ameliorates vascular endothelial cell pyroptosis and dysfunction induced by hyperlipidemia and...

Vascular endothelial dysfunction, a form of chronic endothelial inflammation, frequently occurs in patients with diabetes, hyperlipidemia, and hyperglycemia, which is a key trigger of cardiovascular diseases. Emerging evidence has indicated that pyroptosis plays a crucial role in endothelial dysfunction and potentially represents a promising therapeutic strategy. Punicalin (PUN), a bioactive compound derived from ellagitannins, has demonstrated great potential of anti-inflammatory and anti-pyroptosis. However, the specific protective mechanisms of PUN in vascular endothelial cells remain insufficiently explored. In this study, we developed endothelial dysfunction models to examine the effects of PUN on pyroptosis and endothelial function. Our findings reveal that PUN increases nitric oxide (NO) production, down regulates endothelin-1 (ET-1) levels, and activates the PI3K/Akt/eNOS pathway, thus enhancing endothelial function as evidenced by improving endothelium-dependent vasodilation. Additionally, PUN suppresses the generation of endogenous reactive oxygen species and inhibited the increasing levels of NLRP3, c-caspase-1, GSDMD-N, IL-1β, and IL-18 induced by high fat and high glucose condition, thereby reducing endothelial pyroptosis in both experimental settings. It also promotes phosphorylation of FOXO1 and reduces its accumulation in the nuclear, downregulating the NLRP3-Caspase-1 pathway and preventing FOXO1 from interacting with GSDMD, thereby preventing pyroptosis and ameliorating endothelial dysfunction. In conclusion, our results suggest that PUN alleviates endothelial dysfunction by enhancing the PI3K/Akt/eNOS pathway and suppressing NLRP3-caspase-1-mediated pyroptotic signaling. These findings indicate a potential therapeutic approach for preventing vascular complications in patients with diabetes.