Abstract 9186: Maslinic Acid Alleviates Atherosclerosis by Suppressing Mitochondrial ROS-Dependent NLRP3 Inflammasome Activation in Vascular Endothelial Cells via SIRT1/Nrf2 Pathway

Abstract

Introduction: Maslinic acid (MA), a pentacyclic triterpenoid primarily found in food plants, has exhibited multiple inhibitory effects on proatherogenic factors, such as obesity, dyslipidemia, and inflammation. However, its effect on atherosclerosis remains unknown. In this study, we determined if MA can inhibit atherosclerosis progression and explored the underlying molecular mechanisms. Methods: To assess the anti-atherogenic effect of MA in vivo, ApoE deficient mice were treated with MA contained in high-fat diet for 16 weeks. After treatment, mouse aorta and serum samples were collected to determine atherosclerotic lesions, lipid profile, mitochondrial morphology and expression of related molecules. Additionally, human aortic endothelial cells (HAECs) were treated with ox-LDL to induce the endothelial injury model. Prior to the procedure, vehicle or MA were treated in the absence or presence of a SIRT1 inhibitor nicotinamide (NAM) and an Nrf2 inhibitor ML385. Concurrently, we investigated the effects and mechanisms of MA on mitochondrial dysfunction, oxidative stress injury and apoptosis in HAECs. Results: In vivo, MA conferred an anti-atherosclerotic effect as shown by reduced en face and aortic root sinus lesions size. From the electron microscopic analysis, MA ameliorated the mitochondrial damage in aortic endothelium. MA could promote the protein expression of SIRT1 and Nrf2, and enhance the expression of mitochondrial antioxidant enzymes. In addition, MA suppressed NLRP3 inflammasome activation to reduce apoptosis in vascular endothelium. In vitro, MA could inhibit ox-LDL-induced mitochondrial ROS generation by activating SIRT1/Nrf2 pathway, thereby inhibiting NLRP3 inflammasome activation and apoptosis in HAECs. NAM and ML385 eliminated the MA-mediated endothelial protective effect by restraining the expression of SIRT1 and Nrf2, respectively. Conclusions: In conclusion, our findings suggested that MA ameliorated endothelial apoptosis by suppressing mitochondrial ROS-dependent NLRP3 inflammasome activation via SIRT1/Nrf2 pathway and showed efficacy in exerting an anti-atherogenic effect.