PMID- 30017525
OWN - NLM
STAT- MEDLINE
DCOM- 20190311
LR  - 20190311
IS  - 1874-1754 (Electronic)
IS  - 0167-5273 (Linking)
VI  - 269
DP  - 2018 Oct 15
TI  - Knockdown of Herp alleviates hyperhomocysteinemia mediated atherosclerosis 
      through the inhibition of vascular smooth muscle cell phenotype switching.
PG  - 242-249
LID - S0167-5273(18)33052-3 [pii]
LID - 10.1016/j.ijcard.2018.07.043 [doi]
AB  - BACKGROUND: Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a 
      key role in atherosclerosis. We aimed to investigate whether 
      Homocysteine-responsive endoplasmic reticulum protein (Herp) was involved in VSMC 
      phenotypic switching and affected atheroprogression. METHODS: To assess the role 
      of Herp in homocysteine (Hcy)-associated atherosclerosis, Herp(-/-) and LDLR(-/-) 
      double knockout mice were generated and fed with a high methionine diet (HMD) to 
      induce Hyperhomocysteinemia (HHcy). Atherosclerotic lesions, cholesterol 
      homeostasis, endoplasmic reticulum (ER) stress activation, and the phenotype of 
      VSMCs were assessed in vivo. We used siRNAs to knockdown Herp in cultured VSMCs 
      to further validate our findings in vitro. RESULTS: HMD significantly activated 
      the activating transcription factor 6 (ATF6)/Herp arm of ER stress in LDLR(-/-) 
      mice, and induced the phenotypic switch of VSMCs, with the loss of contractile 
      proteins (SMA and calponin) and an increase of OPN protein. Herp(-/-)/LDLR(-/-) 
      mice developed reduced atherosclerotic lesions in the aortic sinus and the whole 
      aorta when compared with LDLR(-/-) mice. However, Herp deficiency had no effect 
      on diet-induced HHcy and hyperlipidemia. Inhibition of VSMC phenotypic switching, 
      decreased proliferation and collagen accumulation were observed in 
      Herp(-/-)/LDLR(-/-) mice when compared with LDLR(-/-) mice. In vitro experiments 
      demonstrated that Hcy caused VSMC phenotypic switching, promoted cell 
      proliferation and migration; this was reversed by Herp depletion. We achieved 
      similar results via inhibition of ER stress using 4-phenylbutyric-acid (4-PBA) in 
      Hcy-treated VSMCs. CONCLUSION: Herp deficiency inhibits the phenotypic switch of 
      VSMCs and the development of atherosclerosis, thus providing novel insights into 
      the role of Herp in atherogenesis.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Lin, Hui
AU  - Lin H
AD  - Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital of 
      Zhejiang University, Shaoxing 312000, Zhejiang, China; The First Clinical Medical 
      College, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
FAU - Ni, Tingjuan
AU  - Ni T
AD  - Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, China.
FAU - Zhang, Jie
AU  - Zhang J
AD  - The First Clinical Medical College, Wenzhou Medical University, Wenzhou 325000, 
      Zhejiang, China.
FAU - Meng, Liping
AU  - Meng L
AD  - Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital of 
      Zhejiang University, Shaoxing 312000, Zhejiang, China.
FAU - Gao, Feidan
AU  - Gao F
AD  - Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang, China.
FAU - Pan, Sunlei
AU  - Pan S
AD  - Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital of 
      Zhejiang University, Shaoxing 312000, Zhejiang, China.
FAU - Luo, Hangqi
AU  - Luo H
AD  - Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, China.
FAU - Xu, Fukang
AU  - Xu F
AD  - Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital of 
      Zhejiang University, Shaoxing 312000, Zhejiang, China.
FAU - Ru, Guomei
AU  - Ru G
AD  - Medical Research Center, Shaoxing People's Hospital, Shaoxing Hospital of 
      Zhejiang University, Shaoxing 312000, Zhejiang, China.
FAU - Chi, Jufang
AU  - Chi J
AD  - Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital of 
      Zhejiang University, Shaoxing 312000, Zhejiang, China; The First Clinical Medical 
      College, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China. Electronic 
      address: jf_chi@163.com.
FAU - Guo, Hangyuan
AU  - Guo H
AD  - Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital of 
      Zhejiang University, Shaoxing 312000, Zhejiang, China; The First Clinical Medical 
      College, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China. Electronic 
      address: ghangyuan@hotmail.com.
LA  - eng
PT  - Journal Article
DEP - 20180713
PL  - Netherlands
TA  - Int J Cardiol
JT  - International journal of cardiology
JID - 8200291
RN  - 0 (Herpud1 protein, mouse)
RN  - 0 (Membrane Proteins)
SB  - IM
EIN - Int J Cardiol. 2019 Mar 1;278:310. PMID: 30336961
MH  - Animals
MH  - Atherosclerosis/genetics/*metabolism/prevention & control
MH  - Cell Proliferation/physiology
MH  - Cells, Cultured
MH  - Gene Knockdown Techniques/methods
MH  - Genes, Switch/*physiology
MH  - Hyperhomocysteinemia/genetics/*metabolism/prevention & control
MH  - Male
MH  - Membrane Proteins/*deficiency/genetics
MH  - Mice
MH  - Mice, Knockout
MH  - Muscle, Smooth, Vascular/*metabolism
MH  - *Phenotype
OTO - NOTNLM
OT  - Atherosclerosis
OT  - Endoplasmic reticulum stress
OT  - Herp
OT  - Phenotypic switch
OT  - Vascular smooth muscle cell
EDAT- 2018/07/19 06:00
MHDA- 2019/03/12 06:00
CRDT- 2018/07/19 06:00
PHST- 2018/05/09 00:00 [received]
PHST- 2018/06/29 00:00 [revised]
PHST- 2018/07/06 00:00 [accepted]
PHST- 2018/07/19 06:00 [pubmed]
PHST- 2019/03/12 06:00 [medline]
PHST- 2018/07/19 06:00 [entrez]
AID - S0167-5273(18)33052-3 [pii]
AID - 10.1016/j.ijcard.2018.07.043 [doi]
PST - ppublish
SO  - Int J Cardiol. 2018 Oct 15;269:242-249. doi: 10.1016/j.ijcard.2018.07.043. Epub 
      2018 Jul 13.