NF-?B-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase.

ABSTRACT: 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-? (TNF-?) elevated miR-155 biogenesis in cultured VSMCs and vessel segments, which was prevented by NF-?B 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 ?1 (sGC?1) expression and nitric oxide (NO)-dependent cGMP production through targeting the sGC?1 transcript. TNF-?-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-? did not cause VSMC phenotypic modulation and limit NO-induced vasodilation in aortic vessels of miR-155-/- mice. These findings suggest that NF-?B-induced miR-155 impairs the VSMC contractile phenotype and NO-mediated vasorelaxation by downregulating sGC?1 expression. These data suggest that NF-?B-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.

SUBMITTER: Park M 

PROVIDER: S-EPMC6376011 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature