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

Wenfei Yu; Wei Jiang; Wenjing Wu; Guangyu Wang; Dandan Zhao; Chuanzhu Yan; Pengfei Lin

doi:10.1016/j.ejphar.2023.175911

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

Eur J Pharmacol. 2023 Sep 15:955:175911. doi: 10.1016/j.ejphar.2023.175911. Epub 2023 Jul 13.

Authors

Wenfei Yu¹, Wei Jiang², Wenjing Wu³, Guangyu Wang³, Dandan Zhao³, Chuanzhu Yan⁴, Pengfei Lin⁵

Affiliations

¹ Department of Neurology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China; University of Health and Rehabilitation Sciences, No. 17, Shandong Road, Shinan District, Qingdao City, Shandong Province, China.
² Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China.
³ Department of Neurology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China.
⁴ Department of Neurology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China. Electronic address: czyan@sdu.edu.cn.
⁵ Department of Neurology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China. Electronic address: lpfsdu@foxmail.com.

PMID: 37451421
DOI: 10.1016/j.ejphar.2023.175911

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.

Keywords: Atherosclerosis; Idebenone; NLRP3 inflammasome; Oxidative stress.