PMID- 34016263
OWN - NLM
STAT- MEDLINE
DCOM- 20211115
LR  - 20240313
IS  - 1558-3597 (Electronic)
IS  - 0735-1097 (Print)
IS  - 0735-1097 (Linking)
VI  - 77
IP  - 20
DP  - 2021 May 25
TI  - Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in 
      Patients With Cardiovascular Disease.
PG  - 2494-2513
LID - S0735-1097(21)01097-4 [pii]
LID - 10.1016/j.jacc.2021.03.314 [doi]
AB  - BACKGROUND: Obesity is associated with increased cardiovascular risk; however, 
      the potential role of dysregulations in the adipose tissue (AT) metabolome is 
      unknown. OBJECTIVES: The aim of this study was to explore the role of 
      dysregulation in the AT metabolome on vascular redox signaling and cardiovascular 
      outcomes. METHODS: A screen was conducted for metabolites differentially secreted 
      by thoracic AT (ThAT) and subcutaneous AT in obese patients with atherosclerosis 
      (n = 48), and these metabolites were then linked with dysregulated vascular redox 
      signaling in 633 patients undergoing coronary bypass surgery. The underlying 
      mechanisms were explored in human aortic endothelial cells, and their clinical 
      value was tested against hard clinical endpoints. RESULTS: Because ThAT volume 
      was associated significantly with arterial oxidative stress, there were 
      significant differences in sphingolipid secretion between ThAT and subcutaneous 
      AT, with C16:0-ceramide and derivatives being the most abundant species released 
      within adipocyte-derived extracellular vesicles. High ThAT sphingolipid secretion 
      was significantly associated with reduced endothelial nitric oxide 
      bioavailability and increased superoxide generated in human vessels. Circulating 
      C16:0-ceramide correlated positively with ThAT ceramides, dysregulated vascular 
      redox signaling, and increased systemic inflammation in 633 patients with 
      atherosclerosis. Exogenous C16:0-ceramide directly increased superoxide via 
      tetrahydrobiopterin-mediated endothelial nitric oxide synthase uncoupling and 
      dysregulated protein phosphatase 2 in human aortic endothelial cells. High plasma 
      C16:0-ceramide and its glycosylated derivative were independently related with 
      increased risk for cardiac mortality (adjusted hazard ratios: 1.394; 95% 
      confidence interval: 1.030 to 1.886; p = 0.031 for C16:0-ceramide and 1.595; 95% 
      confidence interval: 1.042 to 2.442; p = 0.032 for C16:0-glycosylceramide per 1 
      SD). In a randomized controlled clinical trial, 1-year treatment of obese 
      patients with the glucagon-like peptide-1 analog liraglutide suppressed plasma 
      C16:0-ceramide and C16:0-glycosylceramide changes compared with control subjects. 
      CONCLUSIONS: These results demonstrate for the first time in humans that 
      AT-derived ceramides are modifiable regulators of vascular redox state in 
      obesity, with a direct impact on cardiac mortality in advanced atherosclerosis. 
      (The Interaction Between Appetite Hormones; NCT02094183).
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Akawi, Nadia
AU  - Akawi N
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom; Department of Genetics and Genomics, College 
      of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United 
      Arab Emirates. Electronic address: https://twitter.com/NadiaAkawi.
FAU - Checa, Antonio
AU  - Checa A
AD  - Division of Physiological Chemistry II, Department of Medical Biochemistry and 
      Biophysics, Karolinska Institute, Stockholm, Sweden.
FAU - Antonopoulos, Alexios S
AU  - Antonopoulos AS
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Akoumianakis, Ioannis
AU  - Akoumianakis I
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Daskalaki, Evangelia
AU  - Daskalaki E
AD  - Division of Physiological Chemistry II, Department of Medical Biochemistry and 
      Biophysics, Karolinska Institute, Stockholm, Sweden.
FAU - Kotanidis, Christos P
AU  - Kotanidis CP
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Kondo, Hidekazu
AU  - Kondo H
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Lee, Kirsten
AU  - Lee K
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Yesilyurt, Dilan
AU  - Yesilyurt D
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Badi, Ileana
AU  - Badi I
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Polkinghorne, Murray
AU  - Polkinghorne M
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Akbar, Naveed
AU  - Akbar N
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Lundgren, Julie
AU  - Lundgren J
AD  - Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health 
      and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department 
      of Biomedical Sciences, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Copenhagen, Denmark.
FAU - Chuaiphichai, Surawee
AU  - Chuaiphichai S
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Choudhury, Robin
AU  - Choudhury R
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Neubauer, Stefan
AU  - Neubauer S
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Channon, Keith M
AU  - Channon KM
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom.
FAU - Torekov, Signe S
AU  - Torekov SS
AD  - Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health 
      and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department 
      of Biomedical Sciences, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Copenhagen, Denmark.
FAU - Wheelock, Craig E
AU  - Wheelock CE
AD  - Division of Physiological Chemistry II, Department of Medical Biochemistry and 
      Biophysics, Karolinska Institute, Stockholm, Sweden.
FAU - Antoniades, Charalambos
AU  - Antoniades C
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, Oxford, United Kingdom. Electronic address: antoniad@well.ox.ac.uk.
LA  - eng
SI  - ClinicalTrials.gov/NCT02094183
GR  - CH/F/21/90009/BHF_/British Heart Foundation/United Kingdom
GR  - FS/16/15/32047/BHF_/British Heart Foundation/United Kingdom
GR  - DH_/Department of Health/United Kingdom
GR  - RG/17/10/32859/BHF_/British Heart Foundation/United Kingdom
GR  - PG/13/56/30383/BHF_/British Heart Foundation/United Kingdom
GR  - RG/13/1/30181/BHF_/British Heart Foundation/United Kingdom
GR  - RG/F/21/110040/BHF_/British Heart Foundation/United Kingdom
GR  - CH/16/1/32013/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Am Coll Cardiol
JT  - Journal of the American College of Cardiology
JID - 8301365
RN  - 0 (Ceramides)
RN  - 0 (Sphingolipids)
RN  - 11062-77-4 (Superoxides)
RN  - 839I73S42A (Liraglutide)
SB  - IM
CIN - J Am Coll Cardiol. 2021 May 25;77(20):2514-2516. PMID: 34016264
MH  - Adipose Tissue/*metabolism
MH  - Arteries/*metabolism
MH  - Atherosclerosis/complications/*metabolism/mortality
MH  - Case-Control Studies
MH  - Ceramides/*metabolism
MH  - Endothelium, Vascular/metabolism
MH  - Extracellular Vesicles/metabolism
MH  - Humans
MH  - In Vitro Techniques
MH  - Liraglutide
MH  - Metabolomics
MH  - Obesity/complications/*metabolism
MH  - Oxidative Stress
MH  - Randomized Controlled Trials as Topic
MH  - Sphingolipids/metabolism
MH  - Superoxides/metabolism
PMC - PMC8141611
OTO - NOTNLM
OT  - C16:0-ceramide
OT  - adipose tissue
OT  - cardiovascular disease
OT  - metabolomics
OT  - sphingolipids
OT  - vascular redox state
COIS- Funding Support and Author Disclosures This study was supported by the Novo 
      Nordisk Foundation Tripartite Immunometabolism Consortium Award (NNF15CC0018486), 
      the British Heart Foundation (FS/16/15/32047, PG/13/56/30383, RG/17/10/32859 and 
      RG/F/21/110040) and British Heart Foundation Chair award (CH/16/1/32013), British 
      Heart Foundation Centre of Research Excellence award (RG/13/1/30181), the 
      National Institute for Health Research Oxford Biomedical Research Centre, and the 
      Swedish Heart Lung Foundation (HLF 20180290). The authors have reported that they 
      have no relationships relevant to the contents of this paper to disclose.
EDAT- 2021/05/22 06:00
MHDA- 2021/11/16 06:00
PMCR- 2021/05/25
CRDT- 2021/05/21 05:49
PHST- 2021/02/04 00:00 [received]
PHST- 2021/03/23 00:00 [revised]
PHST- 2021/03/26 00:00 [accepted]
PHST- 2021/05/21 05:49 [entrez]
PHST- 2021/05/22 06:00 [pubmed]
PHST- 2021/11/16 06:00 [medline]
PHST- 2021/05/25 00:00 [pmc-release]
AID - S0735-1097(21)01097-4 [pii]
AID - 10.1016/j.jacc.2021.03.314 [doi]
PST - ppublish
SO  - J Am Coll Cardiol. 2021 May 25;77(20):2494-2513. doi: 10.1016/j.jacc.2021.03.314.