PMID- 35763220
OWN - NLM
STAT- MEDLINE
DCOM- 20220920
LR  - 20220930
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Linking)
VI  - 179
IP  - 20
DP  - 2022 Oct
TI  - Substitution of the SERCA2 Cys(674) reactive thiol accelerates atherosclerosis by 
      inducing endoplasmic reticulum stress and inflammation.
PG  - 4778-4791
LID - 10.1111/bph.15912 [doi]
AB  - BACKGROUND AND PURPOSE: The cysteine(674) (C674) thiol of 
      sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase 2 is easily and irreversibly 
      oxidized under atherosclerotic conditions. However, the contribution of the C674 
      thiol redox status in the development of atherosclerosis remains unclear. Our 
      goal was to elucidate the possible mechanism involved. EXPERIMENTAL APPROACH: 
      Heterozygous SERCA2 C674S knock-in mice in which half of the C674 was substituted 
      by serine (S674) were used to mimic the removal of the reactive C674 thiol, which 
      occurs under pathological conditions. Bone marrow-derived macrophages (BMDMs) and 
      cardiac endothelial cells (ECs) were used for intracellular Ca(2+) , macrophage 
      adhesion, and protein expression analysis. The whole aorta and aortic root were 
      isolated for histological analysis. KEY RESULTS: Cell culture studies suggest the 
      partial substitution of SERCA2 C674 increased intracellular Ca(2+) levels and 
      induced ER stress in both BMDMs and ECs. The release of proinflammatory factors 
      and macrophage adhesion increased in SKI BMDMs. In ECs, overexpression of S674 
      induced endothelial inflammation and promoted macrophage recruitment. SKI mice 
      developed more severe atherosclerotic plaque and macrophage accumulation. 
      Additionally, 4-phenyl butyric acid, an ER stress inhibitor, suppressed ER stress 
      and inflammatory responses in BMDMs and ECs, and alleviated atherosclerosis in 
      SKI mice. CONCLUSIONS AND IMPLICATIONS: The substitution of SERCA2 C674 thiol 
      accelerates the development of atherosclerosis by inducing ER stress and 
      inflammation. Our findings highlight the importance of SERCA2 C674 redox state in 
      the context of atherosclerosis and open up a novel therapeutic strategy to combat 
      atherosclerosis.
CI  - (c) 2022 British Pharmacological Society.
FAU - Su, Hang
AU  - Su H
AUID- ORCID: 0000-0002-3136-5745
AD  - Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School 
      of Pharmaceutical Sciences, Chongqing University, Chongqing, China.
FAU - Mei, Yu
AU  - Mei Y
AUID- ORCID: 0000-0001-6117-7924
AD  - Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University 
      School of Medicine, Boston, Massachusetts, USA.
FAU - Luo, Shuangxue
AU  - Luo S
AUID- ORCID: 0000-0001-9050-1893
AD  - Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School 
      of Pharmaceutical Sciences, Chongqing University, Chongqing, China.
FAU - Wu, Haixia
AU  - Wu H
AUID- ORCID: 0000-0002-6765-5058
AD  - Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School 
      of Pharmaceutical Sciences, Chongqing University, Chongqing, China.
FAU - He, Yan
AU  - He Y
AUID- ORCID: 0000-0002-8101-1072
AD  - Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School 
      of Pharmaceutical Sciences, Chongqing University, Chongqing, China.
FAU - Shiraishi, Yasunaga
AU  - Shiraishi Y
AUID- ORCID: 0000-0001-5901-4026
AD  - Department of Internal Medicine, Division of Cardiovascular Medicine, National 
      Defense Medical College, Saitama, Japan.
FAU - Hu, Pingping
AU  - Hu P
AD  - Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School 
      of Pharmaceutical Sciences, Chongqing University, Chongqing, China.
AD  - College of Pharmacy, Chongqing Medical University, Chongqing, China.
FAU - Cohen, Richard A
AU  - Cohen RA
AUID- ORCID: 0000-0002-1070-6408
AD  - Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University 
      School of Medicine, Boston, Massachusetts, USA.
FAU - Tong, Xiaoyong
AU  - Tong X
AUID- ORCID: 0000-0002-0553-6723
AD  - Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School 
      of Pharmaceutical Sciences, Chongqing University, Chongqing, China.
LA  - eng
GR  - R01 HL031607/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20220721
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Sulfhydryl Compounds)
RN  - 107-92-6 (Butyric Acid)
RN  - 452VLY9402 (Serine)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - EC 7.2.2.10 (Atp2a2 protein, mouse)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - Animals
MH  - *Atherosclerosis/metabolism
MH  - Butyric Acid
MH  - Cysteine/metabolism
MH  - *Endoplasmic Reticulum Stress
MH  - Endothelial Cells/metabolism
MH  - Inflammation/metabolism
MH  - Mice
MH  - *Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism
MH  - Serine
MH  - Sulfhydryl Compounds/metabolism
OTO - NOTNLM
OT  - SERCA2
OT  - atherosclerosis
OT  - endoplasmic reticulum stress
OT  - inflammation
OT  - macrophages
EDAT- 2022/06/29 06:00
MHDA- 2022/09/21 06:00
CRDT- 2022/06/28 11:21
PHST- 2022/05/31 00:00 [revised]
PHST- 2021/01/28 00:00 [received]
PHST- 2022/06/03 00:00 [accepted]
PHST- 2022/06/29 06:00 [pubmed]
PHST- 2022/09/21 06:00 [medline]
PHST- 2022/06/28 11:21 [entrez]
AID - 10.1111/bph.15912 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2022 Oct;179(20):4778-4791. doi: 10.1111/bph.15912. Epub 2022 Jul 
      21.