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

Minsik Park, Seunghwan Choi, Suji Kim, Joohwan Kim, Dong Keon Lee, Wonjin Park, Taesam Kim, Jiwon Jung, Jong Yun Hwang, Moo Ho Won, Sungwoo Ryoo, Seung Goo Kang, Kwon Soo Ha, Young-Guen Kwon, Young Myeong Kim

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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.

Original languageEnglish
Article number17
JournalExperimental and Molecular Medicine
Volume51
Issue number2
DOIs
Publication statusPublished - 2019 Feb 1

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Guanylate Cyclase
MicroRNAs
Vascular Smooth Muscle
Smooth Muscle Myocytes
Muscle
Down-Regulation
Cells
Vasodilation
Nitric Oxide
Tumor Necrosis Factor-alpha
Pre-Eclampsia
Atherosclerosis
Soluble Guanylyl Cyclase
Tunica Intima
Phenotype
Cell proliferation
High Fat Diet
Apolipoproteins E
Nutrition
Cell Movement

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Park, Minsik ; Choi, Seunghwan ; Kim, Suji ; Kim, Joohwan ; Lee, Dong Keon ; Park, Wonjin ; Kim, Taesam ; Jung, Jiwon ; Hwang, Jong Yun ; Won, Moo Ho ; Ryoo, Sungwoo ; Kang, Seung Goo ; Ha, Kwon Soo ; Kwon, Young-Guen ; Kim, Young Myeong. / NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase. In: Experimental and Molecular Medicine. 2019 ; Vol. 51, No. 2.
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title = "NF-κB-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-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.",
author = "Minsik Park and Seunghwan Choi and Suji Kim and Joohwan Kim and Lee, {Dong Keon} and Wonjin Park and Taesam Kim and Jiwon Jung and Hwang, {Jong Yun} and Won, {Moo Ho} and Sungwoo Ryoo and Kang, {Seung Goo} and Ha, {Kwon Soo} and Young-Guen Kwon and Kim, {Young Myeong}",
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Park, M, Choi, S, Kim, S, Kim, J, Lee, DK, Park, W, Kim, T, Jung, J, Hwang, JY, Won, MH, Ryoo, S, Kang, SG, Ha, KS, Kwon, Y-G & Kim, YM 2019, 'NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase', Experimental and Molecular Medicine, vol. 51, no. 2, 17. https://doi.org/10.1038/s12276-019-0212-8

NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase. / Park, Minsik; Choi, Seunghwan; Kim, Suji; Kim, Joohwan; Lee, Dong Keon; Park, Wonjin; Kim, Taesam; Jung, Jiwon; Hwang, Jong Yun; Won, Moo Ho; Ryoo, Sungwoo; Kang, Seung Goo; Ha, Kwon Soo; Kwon, Young-Guen; Kim, Young Myeong.

In: Experimental and Molecular Medicine, Vol. 51, No. 2, 17, 01.02.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase

AU - Park, Minsik

AU - Choi, Seunghwan

AU - Kim, Suji

AU - Kim, Joohwan

AU - Lee, Dong Keon

AU - Park, Wonjin

AU - Kim, Taesam

AU - Jung, Jiwon

AU - Hwang, Jong Yun

AU - Won, Moo Ho

AU - Ryoo, Sungwoo

AU - Kang, Seung Goo

AU - Ha, Kwon Soo

AU - Kwon, Young-Guen

AU - Kim, Young Myeong

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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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