PMID- 34425254
OWN - NLM
STAT- MEDLINE
DCOM- 20220323
LR  - 20220323
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 53
DP  - 2021 Nov
TI  - Salsalate reduces atherosclerosis through AMPKbeta1 in mice.
PG  - 101321
LID - S2212-8778(21)00168-X [pii]
LID - 10.1016/j.molmet.2021.101321 [doi]
LID - 101321
AB  - OBJECTIVE: Salsalate is a prodrug of salicylate that lowers blood glucose in 
      people with type 2 diabetes. AMP-activated protein kinase (AMPK) is an alphabetagamma 
      heterotrimer which inhibits macrophage inflammation and the synthesis of fatty 
      acids and cholesterol in the liver through phosphorylation of acetyl-CoA 
      carboxylase (ACC) and HMG-CoA reductase (HMGCR), respectively. Salicylate binds 
      to and activates AMPKbeta1-containing heterotrimers that are highly expressed in 
      both macrophages and liver, but the potential importance of AMPK and ability of 
      salsalate to reduce atherosclerosis have not been evaluated. METHODS: ApoE(-/-) 
      and LDLr(-/-) mice with or without (-/-) germline or bone marrow AMPKbeta1, 
      respectively, were treated with salsalate, and atherosclerotic plaque size was 
      evaluated in serial sections of the aortic root. Studies examining the effects of 
      salicylate on markers of inflammation, fatty acid and cholesterol synthesis and 
      proliferation were conducted in bone marrow-derived macrophages (BMDMs) from 
      wild-type mice or mice lacking AMPKbeta1 or the key AMPK-inhibitory phosphorylation 
      sites on ACC (ACC knock-in (KI)-ACC KI) or HMGCR (HMGCR-KI). RESULTS: Salsalate 
      reduced atherosclerotic plaques in the aortic roots of ApoE(-/-) mice, but not 
      ApoE(-/-) AMPKbeta1(-/-) mice. Similarly, salsalate reduced atherosclerosis in 
      LDLr(-/-) mice receiving wild-type but not AMPKbeta1(-/-) bone marrow. Reductions in 
      atherosclerosis by salsalate were associated with reduced macrophage 
      proliferation, reduced plaque lipid content and reduced serum cholesterol. In 
      BMDMs, this suppression of proliferation by salicylate required phosphorylation 
      of HMGCR and the suppression of cholesterol synthesis. CONCLUSIONS: These data 
      indicate that salsalate suppresses macrophage proliferation and atherosclerosis 
      through an AMPKbeta1-dependent pathway, which may involve HMGCR phosphorylation and 
      cholesterol synthesis. Since rapidly-proliferating macrophages are a hallmark of 
      atherosclerosis, these data indicate further evaluation of salsalate as a 
      potential therapeutic agent for treating atherosclerotic cardiovascular disease.
CI  - Copyright (c) 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.
FAU - Day, Emily A
AU  - Day EA
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Canada; Department of Medicine, McMaster University, Canada.
FAU - Ford, Rebecca J
AU  - Ford RJ
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Canada; Department of Medicine, McMaster University, Canada.
FAU - Smith, Brennan K
AU  - Smith BK
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Canada; Department of Medicine, McMaster University, Canada.
FAU - Houde, Vanessa P
AU  - Houde VP
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Canada; Department of Medicine, McMaster University, Canada.
FAU - Stypa, Stephanie
AU  - Stypa S
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Canada; Department of Medicine, McMaster University, Canada.
FAU - Rehal, Sonia
AU  - Rehal S
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Canada; Department of Medicine, McMaster University, Canada.
FAU - Lhotak, Sarka
AU  - Lhotak S
AD  - Department of Medicine, McMaster University, Canada; Hamilton Centre for Kidney 
      Research, St. Joseph's Healthcare Hamilton, Canada.
FAU - Kemp, Bruce E
AU  - Kemp BE
AD  - St. Vincent's Institute of Medical Research and Department of Medicine, 
      University of Melbourne, Fitzroy, Victoria, Australia; Mary MacKillop Institute 
      for Health Research, Australian Catholic University, Fitzroy, VIC, Australia.
FAU - Trigatti, Bernardo L
AU  - Trigatti BL
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, 
      Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 
      Canada.
FAU - Werstuck, Geoff H
AU  - Werstuck GH
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, 
      Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 
      Canada.
FAU - Austin, Richard C
AU  - Austin RC
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Canada; Department of Medicine, McMaster University, Canada; Hamilton Centre for 
      Kidney Research, St. Joseph's Healthcare Hamilton, Canada.
FAU - Fullerton, Morgan D
AU  - Fullerton MD
AD  - Department of Biochemistry, Microbiology and Immunology, Centre for Infection, 
      Immunity and Inflammation, Centre for Catalysis Research and Innovation, Faculty 
      of Medicine, University of Ottawa, Canada.
FAU - Steinberg, Gregory R
AU  - Steinberg GR
AD  - Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 
      Canada; Department of Medicine, McMaster University, Canada; Department of 
      Biochemistry and Biomedical Sciences, McMaster University, Canada. Electronic 
      address: gsteinberg@mcmaster.ca.
LA  - eng
SI  - ClinicalTrials.gov/NCT00624923
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210821
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
RN  - 0 (Salicylates)
RN  - EC 2.7.11.1 (Prkab1 protein, mouse)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/deficiency/*metabolism
MH  - Animals
MH  - Atherosclerosis/*metabolism
MH  - Cells, Cultured
MH  - Mice
MH  - Mice, Knockout
MH  - Salicylates/*metabolism
PMC - PMC8429104
OTO - NOTNLM
OT  - Aspirin
OT  - Lipogenesis
OT  - Macrophage
OT  - Proliferation
OT  - Salicylate
OT  - Sterol synthesis
EDAT- 2021/08/24 06:00
MHDA- 2022/03/24 06:00
PMCR- 2021/08/21
CRDT- 2021/08/23 20:15
PHST- 2021/07/04 00:00 [received]
PHST- 2021/07/23 00:00 [revised]
PHST- 2021/08/10 00:00 [accepted]
PHST- 2021/08/24 06:00 [pubmed]
PHST- 2022/03/24 06:00 [medline]
PHST- 2021/08/23 20:15 [entrez]
PHST- 2021/08/21 00:00 [pmc-release]
AID - S2212-8778(21)00168-X [pii]
AID - 101321 [pii]
AID - 10.1016/j.molmet.2021.101321 [doi]
PST - ppublish
SO  - Mol Metab. 2021 Nov;53:101321. doi: 10.1016/j.molmet.2021.101321. Epub 2021 Aug 
      21.