K-80003 Inhibition of Macrophage Apoptosis and Necrotic Core Development in Atherosclerotic Vulnerable Plaques.
K-80003 Inhibition of Macrophage Apoptosis and Necrotic Core Development in Atherosclerotic Vulnerable Plaques.
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K-80003 抑制动脉粥样硬化易损斑块中的巨噬细胞凋亡和坏死核心发育
DOI：
10.1007/s10557-021-07237-4
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发表时间：
2022-12
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
目的巨噬细胞凋亡与吞噬细胞对凋亡细胞的清除缺陷相结合，促进了晚期动脉粥样硬化斑块坏死，从而导致急性动脉粥样硬化血栓性血管疾病。非甾体类抗炎药舒林酸衍生物K-80003治疗先前被报道显著减弱动脉粥样硬化斑块进展和不稳定。然而，其潜在机制尚未完全了解。本研究旨在确定K-80003对巨噬细胞凋亡的作用，并阐明其潜在的mechanism.MethodsThe小鼠模型的颈动脉易损斑块在ApoE−/−小鼠体内开发。因此，将小鼠随机分为两个研究组：对照组和K-80003组（30 mg/kg/天）。收集颈动脉样本，测定动脉粥样硬化坏死核心面积、细胞凋亡和氧化应激。K-80003对RAW264.7巨噬细胞凋亡，氧化应激和自噬通量的影响也在vitro.ResultsK-80003显着抑制坏死核心的形成和抑制易损斑块的细胞凋亡。K-80003在体外也能抑制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巨噬细胞凋亡的关键原因。从机制上讲，K-80003可预防7-酮胆固醇诱导的巨噬细胞自噬通量受损，表现为LC 3 II和SQSTM 1/p62表达降低，结论自噬介导的氧化应激减少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。80003.
PurposeMacrophage 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.MethodsThe 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.ResultsK-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.ConclusionInhibition 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.
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影响因子：
20.1
作者：
Quillard T;Libby P
通讯作者：
Libby P
DOI：
10.1007/s00259-006-0199-y
发表时间：
2007-02-01
影响因子：
9.1
作者：
Cauchon, Nicole;Langlois, Rejean;van Lier, Johan E.
通讯作者：
van Lier, Johan E.
影响因子：
5.3
作者：
BALL, RY;STOWERS, EC;MITCHINSON, MJ
通讯作者：
MITCHINSON, MJ
影响因子：
24
作者：
Falk, E
通讯作者：
Falk, E
DOI：
10.1001/jama.295.13.jpc60002
发表时间：
2006-04-05
影响因子：
120.7
作者：
Nissen, SE;Nicholls, SJ;Tuzcu, EM
通讯作者：
Tuzcu, EM