Macrophage‐derived exosomal miR‐4532 promotes endothelial cells injury by targeting SP1 and NF‐κB P65 signalling activation

Abstract

Atherosclerosis is a complex pathological process involving macrophages, endothelial cells and vascular smooth muscle cells that can lead to ischemic heart disease; however, the mechanisms underlying cell‐to‐cell communication in atherosclerosis are poorly understood. In this study, we focused on the role of exosomal miRNAs in crosstalk between macrophages and endothelial cells and explored the rarely studied molecular mechanisms involved. Our in vitro result showed that macrophage‐derived exosomal miR‐4532 significantly disrupted human umbilical vein endothelial cells (HUVECs) function by targeting SP1 and downstream NF‐κB P65 activation. In turn, increased endothelin‐1 (ET‐1), intercellular cell adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1) and decreased endothelial nitric oxide synthase (eNOS) expression in HUVECs increased attraction of macrophages, exacerbating foam cell formation and transfer of exosomal miR‐4532 to HUVECs. MiR‐4532 overexpression significantly promoted endothelial injury and pretreatment with an inhibitor of miR‐4532 or GW4869 (exosome inhibitor) could reverse this injury. In conclusion, our data reveal that exosomes have a critical role in crosstalk between HUVECs and macrophages. Further, exosomal miR‐4532 transferred from macrophages to HUVECs and targeting specificity protein 1 (SP1) may be a novel therapeutic target in patients with atherosclerosis.

Development and validation of urinary exosomal microRNA biomarkers for the diagnosis of acute rejection in kidney transplant recipients

“…Moreover, its levels are negatively associated with the degree of tubulointerstitial inflammation and long-term renal function decline, thereby suggesting that hsa-miR-4532 may be a biomarker of intra-renal inflammation in kidney diseases ( 72 ). On the other hand, high levels of macrophage-derived exosomal miR-4532 activated NF-kB and promotes endothelial cell injury through inhibiting Sphingosine-1-phosphate expression ( 62 ). Dysregulated expression of circulating hsa-miR-4532 has also been documented in various pathological conditions, such as malignancy, endometriosis, and cerebral infarction ( 63 , 64 , 73 , 74 ).…”

Exosomal microRNA‑4516, microRNA‑203 and SFRP1 are potential biomarkers of acute myocardial infarction

“…Previously published reports and the standards of the International Society for Exosome Vesicles indicate that verification of exosomes can be performed using transmission electron microscopy, WB and particle size analysis, simultaneously ( 34 , 39 ). The size and morphology of exosomes can be objectively observed using transmission electron microscopy.…”

“…Previous sequencing results were analyzed and the top 10 miRNAs with high variance ranking were selected for validation ( Fig. 2A ) ( 34 ). SFRP1 was predicted as the target protein for both miR-4516 and miR-203 using TargetScan software ( Fig.…”

“…The aim was also to identify new markers of AMI by performing correlation analysis between exosomal miRNAs and existing clinical indicators in AMI. Our previous study reported the involvement of miRNAs carried by exosomes in the formation of frontal atherosclerosis ( 34 ). This study will investigate the value of miR-4516 and miR-203 in aiding the diagnosis of acute myocardial infarction and predicting the extent of vascular injury through sequencing analysis.…”

Exosomal Non-Coding RNA Mediates Macrophage Polarization: Roles in Cardiovascular Diseases

“…For example, M2 macrophage-derived EVs containing miR-221-3p promote the proliferation of endothelial cells and inhibit inflammation and apoptosis in AS [118] while miR-199a-5p reduces endothelial cell pyroptosis and mitigates AS progression via the SMARCA4/PODXL/NF-κB signaling pathway [119], providing promising strategies for treating AS. Macrophagederived EVs carrying miR-4532 markedly impaired endothelial cell function by regulating SP1 and downstream NF-κB P65 activation [120]. In AS, MiR-503-5p enhances inflammatory cytokines and adhesion molecules released by macrophages, mediating intercellular communication with endothelial cells and vascular SMCs [121].…”