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ResearchIn-Press PreviewCardiology Open Access | 10.1172/JCI173160

Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation

Boa Kim,1 Wencao Zhao,1 Soon Yew Tang,2 Michael G. Levin,3 Ayon Ibrahim,3 Yifan Yang,3 Emilia M. Roberts,4 Ling Lai,3 Jian Li,3 Richard K. Assoian,5 Garret A. FitzGerald,6 and Zoltan Arany3

1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Kim, B. in: JCI | PubMed | Google Scholar

1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Zhao, W. in: JCI | PubMed | Google Scholar |

1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Yang, Y. in: JCI | PubMed | Google Scholar

1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Li, J. in: JCI | PubMed | Google Scholar

1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Assoian, R. in: JCI | PubMed | Google Scholar

1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by FitzGerald, G. in: JCI | PubMed | Google Scholar

1Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

2Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

3Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

4University of Pennsylvania, Philadelphia, United States of America

5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America

6Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Arany, Z. in: JCI | PubMed | Google Scholar |

Published October 12, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI173160.
Copyright © 2023, Kim et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 12, 2023 - Version history
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Abstract

The metabolic syndrome, today affecting more than 20% of the US population, is a group of five conditions that often co-exist and that strongly predispose to cardiovascular disease. How these conditions are linked mechanistically remains unclear, especially two of these: obesity and elevated blood pressure. Here we show that high fat consumption in mice leads to the accumulation of lipid droplets in endothelial cells throughout the organism, and that lipid droplet accumulation in endothelium suppresses endothelial nitric oxide synthase (eNOS), reduces NO production, elevates blood pressure, and accelerates atherosclerosis. Mechanistically, the accumulation of lipid droplets destabilizes eNOS mRNA and activates an endothelial inflammatory signaling cascade that suppresses eNOS and NO production. Pharmacological prevention of lipid droplet formation reverses the suppression of NO production in cell culture and in vivo, and blunts blood pressure elevation in response to high fat diet. These results highlight lipid droplets as a critical and unappreciated component of endothelial cell biology, explain how lipids increase blood pressure acutely, and provide a mechanistic account for the epidemiological link between obesity and elevated blood pressure.

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graphical abstract
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Version history
  • Version 1 (October 12, 2023): In-Press Preview
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