K-80003 Inhibition of Macrophage Apoptosis and Necrotic Core Development in Atherosclerotic Vulnerable Plaques

© 2021. The Author(s)..

PURPOSE: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

Medienart:

E-Artikel

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

Zur Gesamtaufnahme - volume:36

Enthalten in:

Cardiovascular drugs and therapy - 36(2022), 6 vom: 19. Dez., Seite 1061-1073

Sprache:

Englisch

Beteiligte Personen:

Wang, Xiaolei [VerfasserIn]
Sun, Zhe [VerfasserIn]
Yuan, Ruosen [VerfasserIn]
Zhang, Weifeng [VerfasserIn]
Shen, Yejiao [VerfasserIn]
Yin, Anwen [VerfasserIn]
Li, Yanjie [VerfasserIn]
Ji, Qingqi [VerfasserIn]
Wang, Xia [VerfasserIn]
Li, Yi [VerfasserIn]
Zhang, Min [VerfasserIn]
Pan, Xin [VerfasserIn]
Shen, Linghong [VerfasserIn]
He, Ben [VerfasserIn]

Links:

Volltext

Themen:

184SNS8VUH
4S7931G4PP
Apoptosis
Autophagy
Journal Article
K-80003
Macrophage
Oxidative stress
Sulindac
Vulnerable plaque

Anmerkungen:

Date Completed 16.11.2022

Date Revised 31.10.2023

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1007/s10557-021-07237-4

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM329540157