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Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients With Cardiovascular Disease

Lookup NU author(s): Dr Chris Kotanidis

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2021 The Authors. 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)


Publication metadata

Author(s): Akawi N, Checa A, Antonopoulos AS, Akoumianakis I, Daskalaki E, Kotanidis CP, Kondo H, Lee K, Yesilyurt D, Badi I, Polkinghorne M, Akbar N, Lundgren J, Chuaiphichai S, Choudhury R, Neubauer S, Channon KM, Torekov SS, Wheelock CE, Antoniades C

Publication type: Article

Publication status: Published

Journal: Journal of the American College of Cardiology

Year: 2021

Volume: 77

Issue: 20

Pages: 2494-2513

Print publication date: 25/05/2021

Online publication date: 17/05/2021

Acceptance date: 26/03/2021

Date deposited: 21/12/2022

ISSN (print): 0735-1097

ISSN (electronic): 1558-3597

Publisher: Elsevier Inc.

URL: https://doi.org/10.1016/j.jacc.2021.03.314

DOI: 10.1016/j.jacc.2021.03.314

PubMed id: 34016263


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Funding

Funder referenceFunder name
CH/16/1/32013
FS/16/15/32047
HLF 20180290
National Institute for Health Research Oxford Biomedical Research Centre
NNF15CC0018486
RG/F/21/110040
PG/13/56/30383
RG/13/1/30181
RG/17/10/32859

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