Ilexgenin A inhibits mitochondrial fission and promote Drp1 degradation by Nrf2‐induced PSMB5 in endothelial cells

Abstract

Atherosclerosis (AS) is one of important events involving in the pathological process of coronary artery disease. Many traditional Chinese medicines have been widely used for the treatment of AS. Previous studies have demonstrated that Ilexgenin A (IA) obtained from Ilex hainanensis Merr. could improve AS development. However, its underlying mechanism is still unknown. This study was conducted to explore the possible targets and mechanisms involving in the antiatheroclerosis effect of IA. The results showed IA significantly promoted NO production, reduced reactive oxygen species (ROS) generation, and inflammatory cytokine production induced by palmitate (PA) in endothelial cells, demonstrating IA could improve endothelial dysfunction. Meanwhile, IA dramatically inhibited dynamin-related protein 1 (Drp1) expression and mitochondrial fission induced by PA whereas proteasome inhibitor epoxomicin attenuated its effect on Drp1 expression, indicating IA decreased Drp1 expression with regulation of proteasome. Furthermore, IA also could increase the expression of proteasome subunit beta type5 (PSMB5) and activate nuclear factor-like 2 (Nrf2). Nrf2 knockdown eliminated the induction effect of IA on PSMB5 expression while abrogated its inhibition on ROS generation and mitochondrial fission stimulated by PA. These results demonstrated that IA could promote PSMB5 expression in an Nrf2-dependent manner, resulting in the suppression of mitochondrial fission, and thus improve endothelial dysfunction. These findings laid a foundation to the future development of IA as an agent to the prevention and treatment of AS. K E Y W O R D S endothelial dysfunction, Ilexgenin A, mitochondrial fission, Nrf2

Novel Insights and Current Evidence for Mechanisms of Atherosclerosis: Mitochondrial Dynamics as a Potential Therapeutic Target

“…Resveratrol has been shown to promote mitochondrial fusion and can improve endothelial cells by maintaining mitochondrial membrane proteins and reducing ROS, and may be used in the prevention of atherosclerosis ( Yu et al, 2019 ). Studies have found that Ilexgenin A inhibits palmitate-induced Drp1 expression and mitochondrial fission by regulating proteases, reduces the production of ROS and inflammatory factors, improves endothelial dysfunction, and reduces atherosclerosis ( Zhu et al, 2019 ). Salidroside is considered to be an antioxidant with anti-cardiovascular and vascular protective effects.…”

Stanniocalcin-1 Alleviates Contrast-Induced Acute Kidney Injury by Regulating Mitochondrial Quality Control via the Nrf2 Pathway

“…Nrf2 is relatively inactive under unstressed conditions, by interacting with an inhibitor protein, Keap1, sequestered in the cytosol [36]. Activation of Nrf2 can inhibit the expression of Drp1 and mitochondrial fission, thus promoting mitochondrial fusion and survival in vivo and in vitro studies [37,38]. Other studies also show that increased activity of Nrf2 could decrease mitochondrial dysfunction, ROS generation, and apoptosis and is associated with decreased mitophagy level [39,40].…”

Mechanisms of Atherosclerosis Induced by Postprandial Lipemia

“…Traditional Chinese medicine is also widely used in the intervention of atherosclerosis. Zhu et al found that Ilexgenin A (IA) extracted from Ilex hainanensis can induce endothelial cells to produce NO, reduce the production of inflammatory cytokines and reactive oxygen species, and improve endothelial dysfunction ( 140 , 141 ). In a randomized controlled crossover trial with healthy subjects, the experimental group received HFM and a platycodi radix beverage (AP).…”