%0 Journal Article
%T NF-¦ÊB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase
%J -
%D 2019
%R https://doi.org/10.1038/s12276-019-0212-8
%X Vascular smooth muscle cells (VSMCs) play an important role in maintaining vascular function. Inflammation-mediated VSMC dysfunction leads to atherosclerotic intimal hyperplasia and preeclamptic hypertension; however, the underlying mechanisms are not clearly understood. We analyzed the expression levels of microRNA-155 (miR-155) in cultured VSMCs, mouse vessels, and clinical specimens and then assessed its role in VSMC function. Treatment with tumor necrosis factor-¦Á (TNF-¦Á) elevated miR-155 biogenesis in cultured VSMCs and vessel segments, which was prevented by NF-¦ÊB inhibition. MiR-155 expression was also increased in high-fat diet-fed ApoE£¿/£¿ mice and in patients with atherosclerosis and preeclampsia. The miR-155 levels were inversely correlated with soluble guanylyl cyclase ¦Â1 (sGC¦Â1) expression and nitric oxide (NO)-dependent cGMP production through targeting the sGC¦Â1 transcript. TNF-¦Á-induced miR-155 caused VSMC phenotypic switching, which was confirmed by the downregulation of VSMC-specific marker genes, suppression of cell proliferation and migration, alterations in cell morphology, and NO-induced vasorelaxation. These events were mitigated by miR-155 inhibition. Moreover, TNF-¦Á did not cause VSMC phenotypic modulation and limit NO-induced vasodilation in aortic vessels of miR-155£¿/£¿ mice. These findings suggest that NF-¦ÊB-induced miR-155 impairs the VSMC contractile phenotype and NO-mediated vasorelaxation by downregulating sGC¦Â1 expression. These data suggest that NF-¦ÊB-responsive miR-155 is a novel negative regulator of VSMC functions by impairing the sGC/cGMP pathway, which is essential for maintaining the VSMC contractile phenotype and vasorelaxation, offering a new therapeutic target for the treatment of atherosclerosis and preeclampsia
%U https://www.nature.com/articles/s12276-019-0212-8