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

초록

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

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