KMID : 0620920190510020017
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Experimental & Molecular Medicine 2019 Volume.51 No. 2 p.17 ~ p.17
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NF-¥êB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase
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Park Min-Sik
Choi Seung-Hwan Kim Su-Ji Kim Joo-Hwan Lee Dong-Keon Park Won-Jin Kim Tae-Sam Jung Ji-Won Hwang Jong-Yun Won Moo-Ho Ryoo Sung-Woo Kang Seung-Goo Ha Kwon-Soo Kwon Young-Guen Kim Young-Myeong
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Abstract
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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.
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KEYWORD
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Cell migration, Disease model, RNAi
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