PACAP inhibits high fat-induced NLRP3 inflammasome-mediated pyroptosis in vascular endothelial cells by regulating the SIRT1/ROS pathway.

High-fat diet (HFD)-induced obesity leads endothelial dysfunction and contributes to cardiovascular diseases. NLRP3-mediated pyroptosis plays a key role in endothelial injury induced by HFD. Pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide belonging to the secretin family, has demonstrated diverse beneficial effects. However, its impact on a high-fat-induced pyroptosis remains unexplored. The purpose of this study is to evaluate the effect of PACAP in alleviating high-fat-induced pyroptosis of human umbilical vein endothelial cells (HUVECs) and to elucidate its potential mechanisms. The results show that palmitic acid (PA) induces HUVECs injury and pyroptosis, while PACAP alleviates PA-induced HUVECs injury and pyroptosis. In addition, PACAP also has a protective effect on vascular damage in the thoracic aorta of obese mice. We further found that PACAP reduced PA-induced intracellular Reactive Oxygen Species (ROS) in HUVECs, while also mitigating PA-induced HUVECs pyroptosis. Moreover, PACAP can inhibit PA-induced ROS and pyroptosis through activation of SIRT1, and the effects of PACAP are reversed by a SIRT1 inhibitor. In conclusion, our study demonstrates that PACAP can inhibit PA-induced oxidative stress and pyroptosis in HUVECs, and its action is closely related to the SIRT1 pathway.