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.
Highlights
Endoplasmic reticulum (ER) stress, an adaptive, termed the unfolded protein response (UPR), is an evolutionarily conserved response
Transfection of Human umbilical vein endothelial cells (HUVECs) with a miR-204 mimic, which led to marked increase in miR-204 expression (Supplementary Fig. 1A), resulted in upregulation of the ER stress markers Binding immunoglobulin protein (BIP), C/EBP homologous protein (CHOP), and ATF6, as well as phosphorylation of PERK and elF2α (Fig. 1A; Supplementary Fig. 1B)
Our findings add to the growing appreciation of the role of miR-204 in ER stress in general, and vascular ER stress in particular
Summary
Endoplasmic reticulum (ER) stress, an adaptive, termed the unfolded protein response (UPR), is an evolutionarily conserved response. Recent evidence shows that activation of the ER stress response by tradiational risk factos contributes to the pathogenesis of cardiovascular diseases[3, 4] These studies show that patients and animals with diabetes or hypertension have micro- and macro-vascular complications associated with ER stress induction[5,6,7,8]. MiR-211, which shares an almost identical sequence with miR-204, is induced in a PERK-dependent manner[11] Despite these findings, whether miR-204 leads to vascular dysfunction in an ER stress-dependent manner is not known. In this report we investigated if miR-204 is obligatory for endothelial ER stress and leads to vascular endothelial dysfunction by targeting Sirt[1]
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