Vascular microRNA-204 is remotely governed by the microbiome and impairs endothelium-dependent vasorelaxation by downregulating Sirtuin1

Ajit Vikram; Young-Rae Kim; Santosh Kumar; Qiuxia Li; Modar Kassan; Julia S Jacobs; Kaikobad Irani

doi:10.1038/ncomms12565

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Vascular microRNA-204 is remotely governed by the microbiome and impairs endothelium-dependent vasorelaxation by downregulating Sirtuin1

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Vascular microRNA-204 is remotely governed by the microbiome and impairs endothelium-dependent vasorelaxation by downregulating Sirtuin1

Ajit Vikram, Young-Rae Kim, Santosh Kumar, Qiuxia Li, Modar Kassan, Julia S Jacobs and Kaikobad Irani

Nature communications, Vol.7(1), pp.12565-12565

09/02/2016

DOI: 10.1038/ncomms12565

PMCID: PMC5025761

PMID: 27586459

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Abstract

Gut microbiota promotes atherosclerosis, and vascular endothelial dysfunction, signalled by impaired endothelium-dependent vasorelaxation, is an early marker of atherosclerosis. Here we show that vascular microRNA-204 (miR-204) expression is remotely regulated by the microbiome, and impairs endothelial function by targeting the Sirtuin1 lysine deacetylase (Sirt1). MiR-204 is downregulated, while Sirt1 is upregulated, in aortas of germ-free mice. Suppression of gut microbiome with broad-spectrum antibiotics decreases miR-204, increases Sirt1 and bioavailable vascular nitric oxide, and improves endothelium-dependent vasorelaxation in mouse aortas. Antibiotics curtail aortic miR-204 upregulation, and rescue decline of aortic Sirt1 and endothelium-dependent vasorelaxation, triggered by high-fat diet feeding. Improvement of endothelium-dependent vasorelaxation by antibiotics is lost in mice lacking endothelial Sirt1. Systemic antagonism of miR-204 rescues impaired endothelium-dependent vasorelaxation and vascular Sirt1, and decreases vascular inflammation induced by high-fat diet. These findings reveal a gut microbe-vascular microRNA-Sirtuin1 nexus that leads to endothelial dysfunction.

Human Umbilical Vein Endothelial Cells

Sirtuin 1 - metabolism

Cell Line

Atherosclerosis - genetics

Down-Regulation

Humans

Mice, Inbred C57BL

Sirtuin 1 - biosynthesis

Diet, High-Fat - adverse effects

Male

Gastrointestinal Microbiome - physiology

Aorta - metabolism

Atherosclerosis - metabolism

Mice, Knockout

Vasodilation - genetics

Animals

Gastrointestinal Microbiome - drug effects

Endothelium, Vascular - metabolism

Anti-Bacterial Agents - pharmacology

Mice

MicroRNAs - genetics

Nitric Oxide - metabolism

STAT3 Transcription Factor - metabolism

Details

Title: Subtitle: Vascular microRNA-204 is remotely governed by the microbiome and impairs endothelium-dependent vasorelaxation by downregulating Sirtuin1
Creators: Ajit Vikram - Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA
Young-Rae Kim - Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA
Santosh Kumar - Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA
Qiuxia Li - Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA
Modar Kassan - Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA
Julia S Jacobs - Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA
Kaikobad Irani - Heart and Vascular Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA
Resource Type: Journal article
Publication Details: Nature communications, Vol.7(1), pp.12565-12565
DOI: 10.1038/ncomms12565
PMID: 27586459
PMCID: PMC5025761
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: T32 HL007121 / NHLBI NIH HHS T32 HL007344 / NHLBI NIH HHS
Language: English
Date published: 09/02/2016
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984094574902771

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