MiR-145-5p modulates lipid metabolism and M2 macrophage polarization by targeting PAK7 and regulating β-catenin signaling in hyperlipidemia

Abstract

The present study aims to explore the role of microRNA 145-5p (miR-145-5p) in hyperlipidemia. Using bioinformatics tools and a wide range of function and mechanism assays, we attempted to understand the specific function and potential mechanism of miR-145-5p in hyperlipidemia. A cholesterol-enriched diet induced an increase of serum cholesterol and triacylglycerol but a decrease of serum high-density lipoprotein. MiR-145-5p level was decreased in hyperlipidemia rat models. MiR-145-5p regulated lipid metabolism by antagonizing the alteration of high-density lipoprotein, cholesterol, and triacylglycerol in serum mediated by a cholesterol-enriched diet. In mechanism, miR-145-5p directly bound with p21 protein (RAC1)-activated kinase 7 (PAK7) and negatively regulated mRNA and protein levels of PAK7 in THP-1 cells. Furthermore, miR-145-5p level was negatively associated with PAK7 level in rat cardiac tissues. Finally, overexpression of PAK7 reversed the effects of miR-145-5p on β-catenin activation and M2 macrophages polarization in THP-1 cells. In conclusion, MiR-145-5p modulated lipid metabolism and M2 macrophage polarization by targeting PAK7 and regulating β-catenin signaling in hyperlipidemia, which may provide a potential biomarker for the treatment of hyperlipidemia-induced cardiovascular diseases.

Enhanced Local Delivery of microRNA-145a-5P into Mouse Aorta via Ultrasound-Targeted Microbubble Destruction Inhibits Atherosclerotic Plaque Formation

“…This is also consistent with results reported on miR-145 targeted using adenoviral vectors and nanomaterials . This may be explained by the regulation of smooth muscle cells’ excessive migration and proliferation, which is the primary cause of plaque formation. , Additionally, the regulation of macrophage proliferation and apoptosis to mitigate inflammatory responses may contribute to a similar effect. , Therefore, treatment with CMBs/agomir-145 + UTMD reduces necrotic cores and plaque size, thereby limiting AS. This finding is corroborated by similar results reported in a previous study on plaque treatment with adenovirus-mediated transfection of miR-145 …”

“…15,43 Additionally, the regulation of macrophage proliferation and apoptosis to mitigate inflammatory responses may contribute to a similar effect. 12,44 Therefore, treatment with CMBs/agomir-145 + UTMD reduces necrotic cores and plaque size, thereby limiting AS. This finding is corroborated by similar results reported in a previous study on plaque treatment with adenovirus-mediated transfection of miR-145.…”

mmu-miR-145a-5p Accelerates Diabetic Wound Healing by Promoting Macrophage Polarization Toward the M2 Phenotype

“…Wang et al found that miR-145a-5p regulated microglial polarization and the production of inflammatory cytokines, in which the NF-κB pathway might be involved (17). Chen et al reported that miR-145a-5p modulated the polarization of M2 macrophage by targeting PAK7 and regulating β-catenin signaling in hyperlipidemia (53). Moreover, miR-145a-5p regulates the differentiation of myoblasts, adipocytes, and T cells (15,16,54).…”

Macrophage response mediated by extracellular matrix: recent progress

“…Among the enriched miRNAs in MBVs, three were selected according to the sequencing results. All of these miRNAs, miR-125b-5p [93,94], miR-143-3p [95,96], and miR-145-5p [97][98][99], has been reported to contribute to pro-regenerative macrophage phenotype polarization. miRNA inhibition resulted in gene expression patterns opposite those of macrophages treated with MBVs.…”