title: Vascular microRNA-204 is remotely governed by the microbiome and impairs endothelium-dependent vasorelaxation by downregulating Sirtuin1.
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.
authors: Cardiovascular Division, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Ajit
authors: A
authors: Vikram
authors: Cardiovascular Division, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Young-Rae
authors: YR
authors: Kim
authors: Cardiovascular Division, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Santosh
authors: S
authors: Kumar
authors: Cardiovascular Division, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Qiuxia
authors: Q
authors: Li
authors: Cardiovascular Division, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Modar
authors: M
authors: Kassan
authors: Cardiovascular Division, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Julia S
authors: JS
authors: Jacobs
authors: Cardiovascular Division, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa 52242, USA.|Heart and Vascular Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.
authors: Kaikobad
authors: K
authors: Irani
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000378:metabolism*; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009569:Nitric Oxide / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000378:metabolism*; D014664:Vasodilation / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; C574692:MIRN204 microRNA, mouse; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D009569:Nitric Oxide; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1