MicroRNA-204 promotes vascular endoplasmic reticulum stress and endothelial dysfunction by targeting Sirtuin1

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

doi:10.1038/s41598-017-06721-y

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MicroRNA-204 promotes vascular endoplasmic reticulum stress and endothelial dysfunction by targeting Sirtuin1

Journal article

Open access

Peer reviewed

MicroRNA-204 promotes vascular endoplasmic reticulum stress and endothelial dysfunction by targeting Sirtuin1

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

Scientific reports, Vol.7(1), pp.9308-11

08/24/2017

DOI: 10.1038/s41598-017-06721-y

PMCID: PMC5571183

PMID: 28839162

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Abstract

Endoplasmic reticulum (ER) stress has been implicated in vascular endothelial dysfunction of obesity, diabetes, and hypertension. MicroRNAs play an important role in regulating ER stress. Here we show that microRNA-204 (miR-204) promotes vascular ER stress and endothelial dysfunction by targeting the Sirtuin1 (Sirt1) lysine deacetylase. Pharmacologic ER stress induced by tunicamycin upregulates miR-204 and downregulates Sirt1 in the vascular wall/endothelium in vivo and in endothelial cells in vitro. Inhibition of miR-204 protects against tunicamycin-induced vascular/endothelial ER stress, associated impairment of endothelium-dependent vasorelaxation, and preserves endothelial Sirt1. A miR-204 mimic leads to ER stress and downregulates Sirt1 in endothelial cells. Knockdown of Sirt1 in endothelial cells, and conditional deletion of endothelial Sirt1 in mice, promotes ER stress via upregulation of miR-204, whereas overexpression of Sirt1 in endothelial cells suppresses miR-204-induced ER stress. Furthermore, increase in vascular reactive oxygen species induced by ER stress is mitigated by by miR-204 inhibition. Finally, nutritional stress in the form of a Western diet promotes vascular ER stress through miR-204. These findings show that miR-204 is obligatory for vascular ER stress and ER stress-induced vascular endothelial dysfunction, and that miR-204 promotes vascular ER stress via downregulation of Sirt1.

Animals

Aorta - pathology

Endoplasmic Reticulum Stress

Endothelial Cells - drug effects

Endothelial Cells - pathology

Gene Expression Regulation

Mesenteric Arteries - pathology

Mice, Inbred C57BL

Mice, Knockout

MicroRNAs - metabolism

Sirtuin 1 - antagonists & inhibitors

Tunicamycin - administration & dosage

Details

Title: Subtitle: MicroRNA-204 promotes vascular endoplasmic reticulum stress and endothelial dysfunction by targeting Sirtuin1
Creators: Modar Kassan - Roy J. and Lucille A. Carver College of Medicine
Ajit Vikram - Roy J. and Lucille A. Carver College of Medicine
Qiuxia Li - University of Iowa
Young-Rae Kim - University of Iowa
Santosh Kumar - Roy J. and Lucille A. Carver College of Medicine
Mohanad Gabani - Roy J. and Lucille A. Carver College of Medicine
Jing Liu - Roy J. and Lucille A. Carver College of Medicine
Julia S Jacobs - Roy J. and Lucille A. Carver College of Medicine
Kaikobad Irani - Roy J. and Lucille A. Carver College of Medicine
Resource Type: Journal article
Publication Details: Scientific reports, Vol.7(1), pp.9308-11
DOI: 10.1038/s41598-017-06721-y
PMID: 28839162
PMCID: PMC5571183
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Grant note: T32 HL007344 / NHLBI NIH HHS T32 HL007121 / NHLBI NIH HHS
Language: English
Date published: 08/24/2017
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984312964402771

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