Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China.
School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
Cardiovasc Drugs Ther. 2022 Dec;36(6):1061-1073. doi: 10.1007/s10557-021-07237-4. Epub 2021 Aug 19.
Macrophage apoptosis coupled with a defective phagocytic clearance of the apoptotic cells promotes plaque necrosis in advanced atherosclerosis, which causes acute atherothrombotic vascular disease. Nonsteroidal anti-inflammatory drug sulindac derivative K-80003 treatment was previously reported to dramatically attenuate atherosclerotic plaque progression and destabilization. However, the underlying mechanisms are not fully understood. This study aimed to determine the role of K-80003 on macrophage apoptosis and elucidate the underlying mechanism.
The mouse model of vulnerable carotid plaque in ApoE mice was developed in vivo. Consequently, mice were randomly grouped into two study groups: the control group and the K-80003 group (30 mg/kg/day). Samples of carotid arteries were collected to determine atherosclerotic necrotic core area, cellular apoptosis, and oxidative stress. The effects of K-80003 on RAW264.7 macrophage apoptosis, oxidative stress, and autophagic flux were also examined in vitro.
K-80003 significantly suppressed necrotic core formation and inhibited cellular apoptosis of vulnerable plaques. K-80003 can also inhibit 7-ketocholesterol-induced macrophage apoptosis in vitro. Furthermore, K-80003 inhibited intraplaque cellular apoptosis mainly through the suppression of oxidative stress, which is a key cause of advanced lesional macrophage apoptosis. Mechanistically, K-80003 prevented 7-ketocholesterol-induced impairment of autophagic flux in macrophages, evidenced by the decreased LC3II and SQSTM1/p62 expression, GFP-RFP-LC3 cancellation upon K-80003 treatment.
Inhibition of macrophage apoptosis and necrotic core formation by autophagy-mediated reduction of oxidative stress is one mechanism of the suppression of plaque progression and destabilization by K-80003.
巨噬细胞凋亡伴凋亡细胞吞噬清除功能缺陷可促进晚期动脉粥样硬化斑块坏死，进而导致急性动脉粥样血栓性血管疾病。先前有研究报道，非甾体类抗炎药舒林酸衍生物 K-80003 可显著抑制动脉粥样硬化斑块进展和不稳定。然而，其潜在机制尚不完全清楚。本研究旨在探讨 K-80003 对巨噬细胞凋亡的作用，并阐明其潜在机制。
通过体内载脂蛋白 E（ApoE）小鼠易损颈动脉斑块模型，将小鼠随机分为两组：对照组和 K-80003 组（30mg/kg/天）。收集颈动脉样本以确定动脉粥样硬化坏死核心面积、细胞凋亡和氧化应激情况。还在体外研究了 K-80003 对 RAW264.7 巨噬细胞凋亡、氧化应激和自噬流的影响。
K-80003 显著抑制易损斑块的坏死核心形成和细胞凋亡。K-80003 还可抑制 7-酮胆固醇诱导的巨噬细胞凋亡。此外，K-80003 主要通过抑制氧化应激来抑制斑块内细胞凋亡，氧化应激是晚期病变中巨噬细胞凋亡的关键原因。机制上，K-80003 可防止 7-酮胆固醇诱导的巨噬细胞自噬流受损，表现为 LC3II 和 SQSTM1/p62 表达减少，K-80003 处理后 GFP-RFP-LC3 消失。
通过自噬减轻氧化应激来抑制巨噬细胞凋亡和坏死核心形成是 K-80003 抑制斑块进展和不稳定的机制之一。
