Nuclear Factor Erythroid 2 Related Factor 2 Activator JC-5411 Inhibits Atherosclerosis Through Suppression of Inflammation and Regulation of Lipid Metabolism

Xinhai Jiang; Yining Li; Weizhi Wang; Xiaowan Han; Jiangxue Han; Mingzhu Chen; Jing Zhang; Chenyin Wang; Shunwang Li; Jinque Luo; Xiao Wang; Yang Xu; Yanni Xu; Jingcai Cheng; Shuyi Si

doi:10.3389/fphar.2020.532568

Nuclear Factor Erythroid 2 Related Factor 2 Activator JC-5411 Inhibits Atherosclerosis Through Suppression of Inflammation and Regulation of Lipid Metabolism

Front Pharmacol. 2020 Nov 16:11:532568. doi: 10.3389/fphar.2020.532568. eCollection 2020.

Authors

Xinhai Jiang¹, Yining Li¹, Weizhi Wang¹, Xiaowan Han¹, Jiangxue Han¹, Mingzhu Chen¹, Jing Zhang¹, Chenyin Wang¹, Shunwang Li¹, Jinque Luo¹, Xiao Wang¹, Yang Xu¹, Yanni Xu¹, Jingcai Cheng², Shuyi Si¹

Affiliations

¹ NHC Key Laboratory of Biotechnology of Antibiotics, National Center for New Microbial Drug Screening, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS and PUMC), Beijing, China.
² JC (Wuxi) COMPANY, Inc., Wuxi, China.

Abstract

Phenethyl isothiocyanate is widely present in cruciferous vegetables with multiple biological effects. Here we reported the antiatherogenic effects and the underlying mechanisms of JC-5411 (Phenethyl isothiocyanate formulation) in vitro and in vivo. Luciferase reporter assay showed that JC-5411 increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE). JC-5411 treatment significantly increased the protein expression of Nrf2 and its downstream target gene hemeoxygenase 1 (HO-1) in liver of apolipoprotein E deficient (ApoE^-/-) mice. Importantly, JC-5411 treatment significantly reduced atherosclerotic plaque area in both en face aorta and aortic sinus when compared with model group in WD induced ApoE^-/- mice. JC-5411 obviously decreased proinflammatory factors' levels in serum of ApoE^-/- mice, LPS stimulated macrophages and TNFα induced endothelial cells, respectively. JC-5411 significantly decreased the levels of total cholesterol (TC) and triglyceride (TG) in both serum and liver of ApoE^-/- mice and hyperlipidemic golden hamsters. Mechanism studies showed that JC-5411 exerted anti-inflammatory effect through activating Nrf2 signaling and inhibiting NF-κB and NLRP3 inflammasome pathway. JC-5411 exerted regulating lipid metabolism effect through increasing cholesterol transfer proteins (ABCA1 and LDLR) expression, regulating fatty acids synthesis related genes (p-ACC, SCD1 and FAS), and increasing fatty acids β-oxidation (CPT1A) in vivo. Furthermore, JC-5411 treatment had a favorable antioxidant effect in ApoE^-/- mice by increasing the antioxidant related genes expression. Taken together, we conclude that JC-5411 as a Nrf2 activator has anti-inflammatory, rebalancing lipid metabolism, and antioxidant effects, which makes it as a potential therapeutic agent against atherosclerosis.

Keywords: JC-5411; Phenethyl isothiocyanate; atherosclerosis; inflammation; nuclear factor erythroid 2-related factor 2.