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Cited by 95Cardiovascular Disease and AdiposityPulmonary Hypertension Research and TreatmentsAdipokines, Inflammation, and Metabolic Diseases

Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity

Open access
Kelley, Eric E., Baust, Jeff, Bonacci, Gustavo, Golin-Bisello, Franca, Devlin, Jason E., St. Croix, Claudette M., Watkins, Simon C., Gor, Sonia +7 more·2014·Cardiovascular Research
DOI 10.1093/cvr/cvt341PMC PMC3928004
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Abstract

AIMS: Obesity is a risk factor for diabetes and cardiovascular diseases, with the incidence of these disorders becoming epidemic. Pathogenic responses to obesity have been ascribed to adipose tissue (AT) dysfunction that promotes bioactive mediator secretion from visceral AT and the initiation of pro-inflammatory events that induce oxidative stress and tissue dysfunction. Current understanding supports that suppressing pro-inflammatory and oxidative events promotes improved metabolic and cardiovascular function. In this regard, electrophilic nitro-fatty acids display pleiotropic anti-inflammatory signalling actions. METHODS AND RESULTS: It was hypothesized that high-fat diet (HFD)-induced inflammatory and metabolic responses, manifested by loss of glucose tolerance and vascular dysfunction, would be attenuated by systemic administration of nitrooctadecenoic acid (OA-NO2). Male C57BL/6j mice subjected to a HFD for 20 weeks displayed increased adiposity, fasting glucose, and insulin levels, which led to glucose intolerance and pulmonary hypertension, characterized by increased right ventricular (RV) end-systolic pressure (RVESP) and pulmonary vascular resistance (PVR). This was associated with increased lung xanthine oxidoreductase (XO) activity, macrophage infiltration, and enhanced expression of pro-inflammatory cytokines. Left ventricular (LV) end-diastolic pressure remained unaltered, indicating that the HFD produces pulmonary vascular remodelling, rather than LV dysfunction and pulmonary venous hypertension. Administration of OA-NO2 for the final 6.5 weeks of HFD improved glucose tolerance and significantly attenuated HFD-induced RVESP, PVR, RV hypertrophy, lung XO activity, oxidative stress, and pro-inflammatory pulmonary cytokine levels. CONCLUSIONS: These observations support that the pleiotropic signalling actions of electrophilic fatty acids represent a therapeutic strategy for limiting the complex pathogenic responses instigated by obesity.

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  • NO2-FAs exert pleiotropic post-translational, anti-oxidant and anti-inflammatory effects that include inhibition of vascular smooth muscle proliferation and neointima formation after injury, cardioprotection, improved endothelial function, and activation of downstream NO signaling pathways.

    “NO2-FAs exert pleiotropic post-translational, anti-oxidant and anti-inflammatory effects[105,321,385] that include inhibition of vascular smooth muscle proliferation and neointima formation after injury, cardioprotection, improved endothelial function[94,386–390], and activation of downstream NO signaling pathways[385,389,391–394].”

    From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [391]

  • In a high-fat diet model of PH, Kelley et al. found that mice supplemented with the NO2-FA, nitro-octadecenoic acid, for 6.5 out of 20 weeks on a high-fat diet had reductions in markers of oxidative stress, inflammation, right ventricular remodeling, and degree of pulmonary pressure elevation seen in mice without NO2-FA supplementation on the same high-fat diet.

    “In a high-fat diet model of PH, Kelley et al. found that mice supplemented with the NO2-FA, nitro-octadecenoic acid, for 6.5 out of 20 weeks on a high-fat diet had reductions in markers of oxidative stress, inflammation, right ventricular remodeling, and degree of pulmonary pressure elevation seen in mice without NO2-FA supplementation on the same high-fat diet[391].”

    From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [391]

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1 of the 44 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Hassoun P, Yu F-S, Cote C, Zulueta J, Sawhney R, Skinner KA et al. Upregulation of xan- thine oxidase by lipopolysaccharide, interleukin-1, and hypoxia. Am J Respir Crit Care Med 1998;158:299 -305.
  2. Coles B, Bloodsworth A, Clark SR, Lewis MJ, Cross AR, Freeman BA et al. Nitrolinoleate inhibits superoxide generation, degranulation, and integrin expression by human neutro- phils. Circ Res 2002;91:375 -381.

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Authors
Kelley, E. E., Baust, J., Bonacci, G., Golin-Bisello, F., Devlin, J. E., St. Croix, C. M., Watkins, S. C., Gor, S., Cantu-Medellin, N., Weidert, E. R., Frisbee, J. C., Gladwin, M. T., Champion, H. C., Freeman, B. A., & Khoo, N. K. H.
Affiliations
  • University of Pittsburgh (US)
  • West Virginia University (US)
Corresponding author
Khoo, Nicholas K.H.
ORCID
Venue
Cardiovascular Research
Publisher
Oxford University Press (OUP)
Published
2014-01-02
Volume
101
Issue
3
Pages
352-363
ISSN
  • 0008-6363 (ISSN-L)
  • 1755-3245
DOI
10.1093/cvr/cvt341
PMC
PMC3928004
OpenAlex
W2156798681
Cited by
95
References
44
Citations by year
2026: 3 · 2025: 4 · 2024: 9 · 2023: 7 · 2022: 8 · 2021: 6 · 2020: 7 · 2019: 10 · 2018: 15 · 2017: 8 · 2016: 7 · 2015: 8 · 2014: 3
FWCI
5.96
Type
journal article
Language
en
Open access
Locations
  • Cardiovascular Research (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
  • Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
Funders
  • American Heart Association
  • Gilead Sciences
  • West Virginia University
  • National Institutes of Health (R01-HL-058115, PO1-HL-103455)
  • National Heart, Lung, and Blood Institute (R01HL064937, R37HL058115, R01HL058115, P01HL103455, U01HL108642, UO1-HL-108642-01, R01HL132550)
  • National Institute of General Medical Sciences (U54GM103529)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
high-fat diet-induced obesity, impaired glucose tolerance, pulmonary hypertension, pulmonary vascular remodeling, xanthine oxidoreductase, oxidative stress, adipose tissue inflammation, macrophage infiltration, inflammatory cytokines, right ventricular hypertrophy, anti-inflammatory signaling
MeSH terms
Adipose Tissue, Animals, Blood Glucose, Body Weight, Fatty Acids, Hypertension, Pulmonary, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Obesity, Glucose Intolerance, Mice, Diet, High-Fat

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