PMID- 34660746
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20211022
IS  - 2297-055X (Print)
IS  - 2297-055X (Electronic)
IS  - 2297-055X (Linking)
VI  - 8
DP  - 2021
TI  - Role of PCSK9 in Homocysteine-Accelerated Lipid Accumulation in Macrophages and 
      Atherosclerosis in ApoE(-/-) Mice.
PG  - 746989
LID - 10.3389/fcvm.2021.746989 [doi]
LID - 746989
AB  - Background: Homocysteine (Hcy) has been established as an independent risk factor 
      for atherosclerosis, and the involvement of hyperhomocysteinemia (HHcy) in 
      atherosclerotic lesions is complex. Proprotein convertase subtilisin kexin 9 
      (PCSK9) has vital importance in lipid metabolism, and its inhibitors have intense 
      lipid-lowering and anti-atherosclerotic effects. However, the underlying effect 
      of PCSK9 on HHcy-accelerated dyslipidemia of macrophages is still uncertain. The 
      purpose of this study was to investigate the potential role of PCSK9 in 
      Hcy-induced lipid accumulation and atherosclerotic lesions. Methods: In vitro, 
      gene and protein expressions were assessed by real-time quantitative PCR and 
      western blot in THP-1 macrophages with Hcy incubation. Lipid accumulation and 
      cholesterol efflux were evaluated with Hcy treatment. SBC-115076 was used to 
      examine the role of PCSK9 in ATP-binding cassette transporter A1 and G1 (ABCA1 
      and ABCG1)-dependent cholesterol efflux. In vivo, lesion area, lipid deposition 
      and collagen contents were determined in aortas of ApoE(-/-) mice under a 
      methionine diet. SBC-115076 was subcutaneously injected to explore the potential 
      effects of PCSK9 inhibition on alleviating the severity of HHcy-related 
      atherosclerotic lesions. Results: In THP-1 macrophages, Hcy dose- and 
      time-dependently promoted PCSK9 gene and protein levels without regulating the 
      translation of Low-density lipoprotein receptor (LDLR). SBC-115076 used to 
      inhibit PCSK9 largely alleviated lipid accumulation and reversed the cholesterol 
      efflux to apolipoprotein-I(apoA-I) and high-density lipoprotein (HDL) mediated by 
      ABCA1 and ABCG1. In ApoE(-/-) mice, methionine diet induced HHcy caused larger 
      lesion area and more lipid accumulation in aortic roots. SBC-115076 reduced 
      atherosclerotic severity by reducing the lesion area and lipid accumulation and 
      increasing expressions of ABCA1 and ABCG1 in macrophages from atherosclerotic 
      plaque. In addition, SBC-115076 decreased plasma Hcy level and lipid profiles 
      significantly. Conclusion: PCSK9 promoted lipid accumulation via inhibiting 
      cholesterol efflux mediated by ABCA1 and ABCG1 from macrophages and accelerated 
      atherosclerotic lesions under HHcy treatment. Inhibiting PCSK9 may have 
      anti-atherogenic properties in HHcy-accelerated atherosclerosis.
CI  - Copyright (c) 2021 Jin, Gao, Cong, Yan and Jia.
FAU - Jin, Ping
AU  - Jin P
AD  - Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
FAU - Gao, Dengfeng
AU  - Gao D
AD  - Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
FAU - Cong, Guangzhi
AU  - Cong G
AD  - Heart Center and Cardiovascular Institute, General Hospital of Ningxia Medical 
      University, Yinchuan, China.
FAU - Yan, Ru
AU  - Yan R
AD  - Heart Center and Cardiovascular Institute, General Hospital of Ningxia Medical 
      University, Yinchuan, China.
FAU - Jia, Shaobin
AU  - Jia S
AD  - Heart Center and Cardiovascular Institute, General Hospital of Ningxia Medical 
      University, Yinchuan, China.
LA  - eng
PT  - Journal Article
DEP - 20211001
PL  - Switzerland
TA  - Front Cardiovasc Med
JT  - Frontiers in cardiovascular medicine
JID - 101653388
PMC - PMC8517151
OTO - NOTNLM
OT  - PCSK9
OT  - atherosclerosis
OT  - cholesterol efflux
OT  - homocysteine
OT  - macrophages
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/10/19 06:00
MHDA- 2021/10/19 06:01
PMCR- 2021/01/01
CRDT- 2021/10/18 09:09
PHST- 2021/07/25 00:00 [received]
PHST- 2021/09/03 00:00 [accepted]
PHST- 2021/10/18 09:09 [entrez]
PHST- 2021/10/19 06:00 [pubmed]
PHST- 2021/10/19 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fcvm.2021.746989 [doi]
PST - epublish
SO  - Front Cardiovasc Med. 2021 Oct 1;8:746989. doi: 10.3389/fcvm.2021.746989. 
      eCollection 2021.