Abstract 11676: Atheroprotective Communication Between Endothelial Cells and Smooth Muscle Cells via KLF2-Dependent Enrichment of miRNAs in Microvesicles
The transcription factor Krüppel-like factor 2 (KLF2) was identified as critical mediator of the effects of atheroprotective flow on endothelial cells (ECs). Since miRNAs were shown to play key roles in many pathogenic and physiological processes, we investigated the regulation of miRNAs by KLF2 and flow in ECs. KLF2 regulates the expression of several miRNAs, as assessed by real-time PCR after lentiviral overexpression of KLF2 in HUVECs. Amongst the most up-regulated miRNAs was the miR-143/-145 cluster (miR-143: 16-fold, p<0.001; miR-145: 8-fold, p<0.01), which plays a critical role in modulating vascular smooth muscle cell (SMC) phenotype. Statins, known pharmacological inducers of KLF2, significantly up-regulated the miRNA cluster in vitro (2-fold, p<0.05) and increased endothelial LacZ expression in miR-143/145 reporter mice in vivo. Likewise, prolonged shear stress increased miR-143/-145 (17-fold, p<0.05, 12-fold, p20-fold enriched, p<0.05). Microvesicle-enriched miRNAs are transported to SMCs, as determined by co-culture experiments. KLF2-transduced ECs but not control transduced ECs changed the gene expression pattern of co-cultured SMCs toward a contractile phenotype as shown by a regulation of miR-143/145 targets. In vivo, microvesicles isolated from supernatants of KLF2-expressing ECs reduced atherosclerotic lesion formation in the aorta of ApoE -/- mice. In conclusion, our results show that KLF2 and atheroprotective flow regulate the expression of multiple miRNAs, most prominently miR-143 and miR-145. These miRNAs are enriched in microvesicles and then transferred to SMCs where they regulate miR-143/-145 targets and prevent SMCs de-differentiation. Together, our results provide evidence for atheroprotective communication between ECs and SMCs via a miRNA- and microvesicle-mediated mechanism.
- © 2011 by American Heart Association, Inc.