Combining idebenone and rosuvastatin prevents atherosclerosis by suppressing oxidative stress and NLRP3 inflammasome activation

Abstract

Atherosclerosis is a progressive inflammatory disease activated by excessive oxidized low-density lipoprotein (ox-LDL). Statins are the first-line choice to reduce the risk of cardiovascular disease. However, statin-associated side effects prompt dose reduction or discontinuation. Idebenone could protect against atherosclerosis by scavenging reactive oxygen species (ROS). Although both idebenone and statins have certain efficacy, neither of them can achieve a completely satisfactory effect. Here, we aim to investigate the anti-atherosclerotic effect of the combination of idebenone and statins. Apolipoprotein E knockout (ApoE−/−) mice were given idebenone (400 mg/kg/d), rosuvastatin (10 mg/kg/d) or a combination of idebenone and rosuvastatin. Histological and immunohistochemical staining were used to analyze the size and composition of the plaque. In vivo and in vitro experiments were conducted to explore the possible mechanism. Idebenone and rosuvastatin both reduced plaque burden and increased the stability of atherosclerotic plaques in the ApoE−/− mice. Mice receiving the combination therapy had even reduced and more stable atherosclerotic plaques than mice treated with idebenone or rosuvastatin alone. NLRP3 and IL-1β were further downregulated in mice receiving combination therapy compared with mice treated with monotherapy. The combination treatment also markedly reduced oxidative stress and cell apoptosis in vivo and in vitro. In conclusion, our data demonstrate that the combination of idebenone and rosuvastatin works synergistically to inhibit atherosclerosis, and that the use of both substances together is more effective than using either substance alone. From a therapeutic point, combining idebenone and rosuvastatin appears to be a promising strategy to further prevent atherosclerosis.