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

Abstract

Many attempts to modulate leukocyte-endothelial interaction to prevent or reduce excessive inflammatory reactions were made in the past. However, the basic regulatory principles of the endothelial inflammatory process remain unclear. It seems that the inhibition of individual components of the inflammatory cascade, for example, by a single antibody against an adhesion molecule, may not be enough to achieve a sustained effect on vascular inflammation.In the past years, microRNAs have been identified as important regulators of gene expression in a wide range of Molecular Medicine© 2017 American Heart Association, Inc. 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 a 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. Mechanistically, miR-100 directly repressed several components of mammalian target of rapamycin complex 1-signaling, including mammalian target of rapamycin and raptor, which resulted in a stimulation of endothelial autophagy and attenuated nuclear factor κB signaling in vitro and in vivo. In a low-density lipoprotein receptordeficient atherosclerotic mouse model, pharmacological 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 >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 mammalian target of rapamycin signaling and autophagy

MicroRNA‐188 regulates aging‐associated metabolic phenotype

“…MicroRNAs (miRNAs) belong to a class of short noncoding regulatory RNAs (22–24 nucleotides) (Li et al, ; Treiber, Treiber, & Meister, ; Wang et al, 2015; Su et al, ), which exert their functions by binding to the 3' untranslated region (3' UTR) or protein coding sequence of target mRNAs (Frankel et al, ; Thomou et al, ). MiRNAs play crucial roles in regulating many metabolic diseases (Hanin et al, ; Langlet et al, ; Pankratz et al, ; Yu et al, ; Zhang et al, ). However, the role of miRNAs in the regulation of the aging‐associated metabolic phenotype is unknown.…”

MiR‐181a inhibits vascular inflammation induced by ox‐LDL via targeting TLR4 in human macrophages

“…Many recent studies have indicated that miRNAs can control a lot of fundamental biological processes (Rajman & Schratt, ; Zhang et al, ). For example, miR‐100 can inhibit chronic vascular inflammation by stimulating endothelial autophagy (Pankratz et al, ). miR‐126 can alleviate endothelial cells injury in atherosclerosis via inhibition of PI3 K/Akt/mTOR pathway (Tang & Yang, ).…”

Comprehensive Profiling of the Circulatory miRNAome Response to a High Protein Diet in Elderly Men: A Potential Role in Inflammatory Response Modulation

“…miR‐100 is reported to suppress the regulation of IGF‐1R/mTOR pathway by directly targeting mechanistic target of rapamycin ( mTOR ), leading to inhibited cell growth and proliferation . A recent study by Pankratz et al., using both in vitro and in vivo models identified anti‐inflammatory effects of miR‐100 in vascular endothelium by suppressing endothelial adhesion molecule ( ICAM‐1, VCAM‐1 and E‐Selectin ) directly targeting two individual components of the mTORC1 complex ( mTOR and Raptor ). mTOR plays an important role in regulating cell growth .…”