Abstract
Introduction: NLRP3 inflammasome mediated inflammatory factors secretion is critically involved in atherosclerosis (AS). Melatonin has anti-inflammatory properties. However, it is unknown whether melatonin is beneficial in AS. Hypothesis: Melatonin plays a beneficial role in AS by decreasing NLRP3 inflammasome activation in macrophages. Methods: AS model was induced with high fat diet in apoE -/- mice. Plaque stability was examined with historical staining. In vitro study was performed in ox-LDL treated RAW264.7 cells. NLRP3 inflammasome activation, inflammatory factors secretion, mitochondrial ROS generation, autophagy, mitophagy indexes and potential signaling pathways were investigated. Results: Historical staining results showed that melatonin treatment markedly alleviated AS plaque progression. Despite of unchanged protein expression, Sirt 3 activity was elevated in plaque tissue in melatonin treated mice. Melatonin attenuated NLRP3 inflammasome activation and inflammatory factors secretion in ox-LDL treated macrophages, while this protective effect was abolished by Sirt3-siRNA. Mitochondrial ROS (mitoROS), which was an inducer for NLRP3 inflammasome, was reduced by melatonin through the elimination of damaged mitochondria (mitophagy). Similar with Sirt3-siRNA, autophagy inhibitor 3-MA also abolished the effects of melatonin on mitoROS clearance, indicating the crucial role of autophagy and mitophagy in melatonin caused NLRP3 inactivation. Furthermore, melatonin protected against AS via Sirt3/FoxO3/Parkin signaling pathway. Conclusions: Melatonin prevented atherosclerotic progression. Melatonin reduced mitochondrial ROS through the activation of autophagy and mitophagy, thereby attenuating NLRP3 inflammasome activation in macrophages. Moreover, the protective effect of melatonin was mediated by Sirt3/FoxO3/Parkin signaling pathway. Our study provides insight into a new therapeutic target for AS.
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