MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy
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.
- Received June 22, 2017.
- Revision received November 13, 2017.
- Accepted December 1, 2017.