MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy.

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MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy.

Circ Res. 2017 Dec 05;:

Authors: Pankratz F, Hohnloser C, Bemtgen X, Jaenich C, Kreuzaler S, Hoefer IE, Pasterkamp G, Mastroianni J, Zeiser R, Smolka C, Schneider LA, Martin J, Juschkat M, Helbing T, Moser M, Bode C, Grundmann S

Abstract
Rationale: The interaction of circulating cells within the vascular wall is a critical event in chronic inflammatory processes such as atherosclerosis, but the control of the vascular inflammatory state is still largely unclear. Objective: This study was undertaken to characterize the function of the endothelial-enriched microRNA miR-100 during vascular inflammation and atherogenesis. Methods and Results: Based on a transcriptome analysis of endothelial cells after miR-100 overexpression, we identified miR-100 as potent suppressor of endothelial adhesion molecule expression, resulting in attenuated leukocyte-endothelial interaction in vitro and in vivo as shown by flow cytometry and intravital imaging approach. Mechanistically, miR-100 directly repressed several components of mTORC1-signalling, including mTOR and raptor, which resulted in a stimulation of endothelial autophagy and attenuated NF-κB signaling in vitro and in vivo. In a LDLR-deficient atherosclerotic mouse model, pharmacologic inhibition of miR-100 resulted in enhanced plaque lesion formation and a higher macrophage content of the plaque, whereas a systemic miR-100 replacement therapy had protective effects and attenuated atherogenesis, resulting in a decrease of plaque area by 45%. Finally, analysis of miR-100 expression in more than 70 samples obtained during carotid endarterectomy revealed that local miR-100 expression was inversely correlated with inflammatory cell content in patients. Conclusions: In summary, we describe an anti-inflammatory function of miR-100 in the vascular response to injury and inflammation and identify an important novel modulator of mTOR signaling and autophagy in the vascular system. Our findings of miR-100 as a potential protective "anti-athero-miR" suggest that the therapeutic replacement of this miRNA could be a potential strategy for the treatment of chronic inflammatory diseases such as atherosclerosis in the future.

PMID: 29208678 [PubMed - as supplied by publisher]

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