Page 17 - Y. Vascular biology

NF-κB-responsive microRNA-155 induces functional impairment of
VSMCs by downregulating soluble guanylyl cyclase.

Minsik Park , Wonjin Park , Suji Kim , Taesam Kim , Young-Guen Kwon and Young-Myeong Kim a
a
a
b
a
a
a Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do, South Korea
b Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
BACKGROUND AIM
NF-κB-responsive miR-155 has been implicated in endothelial
The interaction or communication between endothelial cells and vascular dysfunction, atherosclerosis, and vascular inflammation and permeability.
smooth muscle cells (VSMCs) plays crucial roles in regulating vascular However, little is known about the involvement of miR-155 in regulating
function, such as vascular remodeling and relaxation, through eNOS-derived VSMC function and phenotypic switching associated with hypertension
NO/sGC pathway. In addition to endothelial dysfunction, phenotypic switching and intimal hyperplasia. Here, we found that miR-155 is upregulated in
of VSMCs from a ‘contractile’ to a pathological ‘synthetic’ state has been patients with atherosclerosis and preeclampsia and facilitates phenotypic
shown to play an important role in the pathogenesis of many human diseases, and functional alterations of VSMCs via inhibition of sGC/cGMP axis
such as atherosclerosis, hypertension, and preeclampsia. Although the activity by downregulating sGCβ1 expression, a subunit of dimeric sGC.
expression of sGC is downregulated by inflammatory cytokines, the
association between sGC downregulation and VSMC dysfunction is poorly These findings suggest that TNF-α-induced miR-155 is a molecular risk
understood in inflammatory disease states. factor for atherosclerotic intima formation and preeclamptic hypertension
by impairing the sGC/cGMP pathway.
METHODS

Treatment with 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. MiR-155 levels were inversely correlated with sGCβ1 expression and NO-dependent cGMP production through
targeting of the sGCβ1 transcript. TNF-α-induced miR-155 caused VSMC phenotypic switching, as confirmed by the
downregulation of VSMC-specific marker genes, suppression of cell proliferation and migration, alterations in cell morphology,
and NO-induced vasorelaxation.

RESULTS

Figure 1. Figure 2. Figure 3.
Different effects of TNF-α-induced miR-31 and MiR-155 and sGCβ1 are differentially TNF-α inhibits sGCβ1 expression through the
miR-155 on NO and cGMP production in expressed in HFD-fed ApoE -/- mice and biogenesis of NF-κB-responsive miR-155.
HUVECs. atherosclerotic and preeclamptic patients.

Figure 4. Figure 5. Figure 6.
MiR-155 inhibits sGCβ1 expression by TNF-α-induced miR-155 exerts VSMC MiR-155 suppresses vasorelaxation by
targeting the 3’-UTR of its transcript. phenotypic switching. impairing the sGC/cGMP pathway.

CONCLUSION REFERENCES ACKNOWLEDGEMENTS

Lee KS, Kim J, Kwak SN, Lee KS, Lee DK, Ha KS, Won MH, This work was supported by National Research
Jeoung D, Lee H, Kwon YG, Kim YM. (2014) Functional role of Foundation of Korea (NRF) grants funded by the
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