The vascular response to pro-atherosclerotic factors is a multifactorial process involving endothelial cells (ECs), macrophages (MACs), and smooth muscle cells (SMCs), although the mechanism by which these cell types communicate with each other in response to environmental cues is yet to be understood. Here, we show that miR-155, which is significantly expressed and secreted in Krüppel-like factor 5 (KLF5)-overexpressing vascular smooth muscle cells (VSMCs), is a potent regulator of endothelium barrier function through regulating endothelial targeting tight junction protein expression. VSMCs-derived exosomes mediate the transfer of KLF5-induced miR-155 from SMCs to ECs, which, in turn, destroys tight junctions and the integrity of endothelial barriers, leading to an increased endothelial permeability and enhanced atherosclerotic progression. Moreover, overexpression of miR-155 in ECs inhibits endothelial cell proliferation/migration and re-endothelialization in vitro and in vivo and thus increases vascular endothelial permeability. Blockage of the exosome-mediated transfer of miR-155 between these two cells may serve as a therapeutic target for atherosclerosis.

MicroRNAs are phenotypic regulators of vascular smooth muscle cells (VSMCs). In this paper, we demonstrate that miR‐146a targets the Krüppel‐like factor 4 ( KLF4 ) 3′‐untranslated region and has an important role in promoting VSMC proliferation in vitro and vascular neointimal hyperplasia in vivo . Silencing of miR‐146a in VSMCs increases KLF4 expression, whereas overexpression of miR‐146a decreases KLF4 levels. Furthermore, we demonstrate that KLF4 competes with Krüppel‐like factor 5 (KLF5) to bind to and regulate the miR‐146a promoter, and that KLF4 and KLF5 exert opposing effects on the miR‐146a promoter. Overexpression of KLF4 in VSMCs decreases miR‐146a transcription levels. By using both gain‐of‐function and loss‐of‐function approaches, we found that miR‐146a promotes VSMC proliferation in vitro . Transfection of antisense miR‐146a oligonucleotide into balloon‐injured rat carotid arteries markedly decreased neointimal hyperplasia. These findings suggest that miR‐146a and KLF4 form a feedback loop to regulate each other's expression and VSMC proliferation.

P53, circRNAs and miRNAs are important components of the regulatory network that activates the EMT program in cancer metastasis. In prostate cancer (PCa), however, it has not been investigated whether and how p53 regulates EMT by circRNAs and miRNAs. Here we show that a Amotl1-derived circRNA, termed circAMOTL1L, is downregulated in human PCa, and that decreased circAMOTL1L facilitates PCa cell migration and invasion through downregulating E-cadherin and upregulating vimentin, thus leading to EMT and PCa progression. Mechanistically, we demonstrate that circAMOTL1L serves as a sponge for binding miR-193a-5p in PCa cells, relieving miR-193a-5p repression of Pcdha gene cluster (a subset of the cadherin superfamily members). Accordingly, dysregulation of the circAMOTL1L-miR-193a-5p-Pcdha8 regulatory pathway mediated by circAMOTL1L downregulation contributes to PCa growth in vivo. Further, we show that RBM25 binds directly to circAMOTL1L and induces its biogenesis, whereas p53 regulates EMT via direct activation of RBM25 gene. These findings have linked p53/RBM25-mediated circAMOTL1L-miR-193a-5p-Pcdha regulatory axis to EMT in metastatic progression of PCa. Targeting this newly identified regulatory axis provides a potential therapeutic strategy for aggressive PCa.

Nuclear actin is involoved in the transcription of all three RNA polymerases, in chromatin remodeling and in the formation of heterogeneous nuclear ribonucleoprotein complexes, as well as in recruitment of the histone modifier to the active gene. In addition, actin‐binding proteins (ABPs) control actin nucleation, bundling, filament capping, fragmentation and monomer availability in the cytoplasm. In recent years, more and more attention has focused on the role of actin and ABPs in the modulation of the subcellular localization of transcriptional regulators. This review focuses on recent developments in the study of transcription and transcriptional regulation by nuclear actin, and the regulation of muscle‐specific gene expression, nuclear receptor and transcription complexes by ABPs. Among the ABPs, striated muscle activator of Rho signaling and actin‐binding LIM protein regulate actin dynamics and serum response factor‐dependent muscle‐specific gene expression. Functionally and structurally unrelated cytoplasmic ABPs interact cooperatively with nuclear receptor and regulate its transactivation. Furthermore, ABPs also participate in the formation of transcription complexes.

Rationale:: Neuregulin-1 (NRG-1) includes an extracellular epidermal growth factor–like domain and an intracellular domain (NRG-1-ICD). In response to transforming growth factor-β1, its cleavage by proteolytic enzymes releases a bioactive fragment, which suppresses the vascular smooth muscle cell (VSMC) proliferation by activating ErbB (erythroblastic leukemia viral oncogene homolog) receptor. However, NRG-1-ICD function in VSMCs remains unknown. Objective:: Here, we characterize the function of NRG-1-ICD and underlying mechanisms in VSMCs. Methods and Results:: Immunofluorescence staining, Western blotting, and quantitative real-time polymerase chain reaction showed that NRG-1 was expressed in rat, mouse, and human VSMCs and was upregulated and cleaved in response to transforming growth factor-β1. In the cytoplasm of HASMCs (human aortic smooth muscle cells), the NRG-1-ICD participated in filamentous actin formation by interacting with α-SMA (smooth muscle α-actin). In the nucleus, the Nrg-1-ICD induced circular ACTA2 (alpha-actin-2; circACTA2) formation by recruitment of the zinc-finger transcription factor IKZF1 (IKAROS family zinc finger 1) to the first intron of α-SMA gene. We further confirmed that circACTA2, acting as a sponge binding microRNA (miR)-548f-5p, interacted with miR-548f-5p targeting 3′ untranslated region of α-SMA mRNA, which in turn relieves miR-548f-5p repression of the α-SMA expression and thus upregulates α-SMA expression, thereby facilitating stress fiber formation and cell contraction in HASMCs. Accordingly, in vivo studies demonstrated that the localization of the interaction of circACTA2 with miR-548f-5p is significantly decreased in human intimal hyperplastic arteries compared with normal arteries, implicating that dysregulation of circACTA2 and miR-548f-5p expression is involved in intimal hyperplasia. Conclusions:: These results suggest that circACTA2 mediates NRG-1-ICD regulation of α-SMA expression in HASMCs via the NRG-1-ICD/circACTA2/miR-548f-5p axis. Our data provide a molecular basis for fine-tuning α-SMA expression and VSMC contraction by transcription factor, circular RNA, and microRNA.