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

Nat Commun. 2016 Sep 2;7:12565. doi: 10.1038/ncomms12565.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Aorta / metabolism*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Cell Line
  • Diet, High-Fat / adverse effects
  • Down-Regulation
  • Endothelium, Vascular / metabolism*
  • Gastrointestinal Microbiome / drug effects
  • Gastrointestinal Microbiome / physiology*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Nitric Oxide / metabolism
  • STAT3 Transcription Factor / metabolism
  • Sirtuin 1 / biosynthesis
  • Sirtuin 1 / metabolism*
  • Vasodilation / genetics*

Substances

  • Anti-Bacterial Agents
  • MIRN204 microRNA, mouse
  • MicroRNAs
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Nitric Oxide
  • Sirt1 protein, mouse
  • Sirtuin 1