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 ()
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Ajit Vikram: University of Iowa Carver College of Medicine
Young-Rae Kim: University of Iowa Carver College of Medicine
Santosh Kumar: University of Iowa Carver College of Medicine
Qiuxia Li: University of Iowa Carver College of Medicine
Modar Kassan: University of Iowa Carver College of Medicine
Julia S. Jacobs: University of Iowa Carver College of Medicine
Kaikobad Irani: University of Iowa Carver College of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12565

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