PMID- 32091078
OWN - NLM
STAT- MEDLINE
DCOM- 20200720
LR  - 20200720
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Linking)
VI  - 134
IP  - 5
DP  - 2020 Mar 13
TI  - Myriocin and d-PDMP ameliorate atherosclerosis in ApoE-/- mice via reducing lipid 
      uptake and vascular inflammation.
PG  - 439-458
LID - 10.1042/CS20191028 [doi]
AB  - Sphingolipids have been implicated in the etiology of atherosclerosis. The 
      commonly used sphingolipid inhibitors, myriocin (a ceramide inhibitor) and d-PDMP 
      (d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, a glycosphingolipid 
      inhibitor), have shown therapeutic potential but their efficacy and their 
      underlying mechanisms remain unclear. Here, apolipoprotein E-deficient (apoE-/-) 
      mice were fed a high-fat diet (HFD) and treated with a control, myriocin, d-PDMP, 
      or atorvastatin for 12 weeks. We analyzed the effects of these drugs on the size 
      and detailed composition of atherosclerotic plaques. Molecular biological 
      approaches were used to explore how the inhibitors affect lipid metabolism and 
      foam-cell formation. Treatment with myriocin or d-PDMP led to smaller and less 
      vulnerable atherosclerotic lesions and was almost as effective as atorvastatin. 
      Sphingolipid inhibitors down-regulated the expression of monocyte chemotactic 
      protein 1 (MCP-1) and its receptor chemoattractant cytokine receptor 2 (CCR2), 
      which play a key role in monocyte recruitment. They also decreased 
      pro-inflammatory Ly-6chigh monocytes and influenced the uptake of modified LDL by 
      down-regulating the expression of cluster of differentiation 36 (CD36) and 
      lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1). The inhibitors exhibited 
      the advantage of maintaining normal glucose homeostasis compared with 
      atorvastatin. These findings reveal for the first time that the modulation of 
      sphingolipid synthesis can effectively alleviate atherosclerosis progression by 
      preventing lipid uptake and reducing inflammatory responses in the arterial 
      walls.
CI  - (c) 2020 The Author(s).
FAU - Yu, Zemou
AU  - Yu Z
AD  - Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, 
      Xicheng District, Beijing 100034, China.
FAU - Peng, Qing
AU  - Peng Q
AD  - Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, 
      Xicheng District, Beijing 100034, China.
FAU - Li, Songyue
AU  - Li S
AD  - Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic 
      Chemistry and Molecular Engineering of Ministry of Education, Institute of 
      Analytical Chemistry, College of Chemistry and Molecular Engineering, Peking 
      University, Beijing 100871, China.
FAU - Hao, Hongjun
AU  - Hao H
AD  - Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, 
      Xicheng District, Beijing 100034, China.
FAU - Deng, Jianwen
AU  - Deng J
AD  - Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, 
      Xicheng District, Beijing 100034, China.
FAU - Meng, Lingbing
AU  - Meng L
AD  - Department of Neurology, Beijing Hospital, National Center of Gerontology, No.1 
      Dahua Road, Dong Dan, Beijing 100730, China.
FAU - Shen, Zhiyuan
AU  - Shen Z
AD  - Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, 
      Xicheng District, Beijing 100034, China.
FAU - Yu, Weiwei
AU  - Yu W
AD  - Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, 
      Xicheng District, Beijing 100034, China.
FAU - Nan, Ding
AU  - Nan D
AD  - Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, 
      Xicheng District, Beijing 100034, China.
FAU - Bai, Yu
AU  - Bai Y
AD  - Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic 
      Chemistry and Molecular Engineering of Ministry of Education, Institute of 
      Analytical Chemistry, College of Chemistry and Molecular Engineering, Peking 
      University, Beijing 100871, China.
FAU - Huang, Yining
AU  - Huang Y
AD  - Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, 
      Xicheng District, Beijing 100034, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Ceramides)
RN  - 0 (Fatty Acids, Monounsaturated)
RN  - 0 (Glycosphingolipids)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Lipids)
RN  - 0 (Morpholines)
RN  - 73257-80-4 (RV 538)
RN  - A0JWA85V8F (Atorvastatin)
RN  - YRM4E8R9ST (thermozymocidin)
SB  - IM
MH  - Animals
MH  - Anticholesteremic Agents/pharmacology
MH  - Apolipoproteins E/*deficiency/genetics
MH  - Atherosclerosis/metabolism/*prevention & control
MH  - Atorvastatin/pharmacology
MH  - Biological Transport/drug effects
MH  - Ceramides/antagonists & inhibitors/metabolism
MH  - Fatty Acids, Monounsaturated/*pharmacology
MH  - Glycosphingolipids/antagonists & inhibitors/metabolism
MH  - Immunosuppressive Agents/pharmacology
MH  - Lipid Metabolism/*drug effects
MH  - Lipids/blood/pharmacokinetics
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Morpholines/*pharmacology
MH  - Plaque, Atherosclerotic/metabolism/pathology/prevention & control
MH  - Vasculitis/metabolism/*prevention & control
OTO - NOTNLM
OT  - atherosclerosis
OT  - inflammation
OT  - lipid uptake
OT  - sphingolipid inhibitors
EDAT- 2020/02/25 06:00
MHDA- 2020/07/21 06:00
CRDT- 2020/02/25 06:00
PHST- 2019/10/06 00:00 [received]
PHST- 2020/02/17 00:00 [revised]
PHST- 2020/02/21 00:00 [accepted]
PHST- 2020/02/25 06:00 [pubmed]
PHST- 2020/07/21 06:00 [medline]
PHST- 2020/02/25 06:00 [entrez]
AID - 222190 [pii]
AID - 10.1042/CS20191028 [doi]
PST - ppublish
SO  - Clin Sci (Lond). 2020 Mar 13;134(5):439-458. doi: 10.1042/CS20191028.