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Exp Mol Med. 2019 Feb 15;51(2):17. doi: 10.1038/s12276-019-0212-8.

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

Author information

1
Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do, 24341, South Korea.
2
Departments of Obstetrics and Gynecology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do, 24341, South Korea.
3
Departments of Neurobiology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do, 24341, South Korea.
4
Department of Biology, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, 24341, South Korea.
5
Department of Systems Immunology, College of Biomedical Science, Kangwon National University, Chuncheon, Gangwon-do, 24341, South Korea.
6
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea.
7
Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do, 24341, South Korea. ymkim@kangwon.ac.kr.

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-α (TNF-α) elevated miR-155 biogenesis in cultured VSMCs and vessel segments, which was prevented by NF-κB 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 β1 (sGCβ1) expression and nitric oxide (NO)-dependent cGMP production through targeting the sGCβ1 transcript. TNF-α-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-α did not cause VSMC phenotypic modulation and limit NO-induced vasodilation in aortic vessels of miR-155-/- mice. These findings suggest that NF-κB-induced miR-155 impairs the VSMC contractile phenotype and NO-mediated vasorelaxation by downregulating sGCβ1 expression. These data suggest that NF-κB-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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