Page 16 - Y. Vascular biology

[Y. Vascular biology-9]

NF-kappaB responsive miR-31-5p elicits endothelial

dysfunction associated with preeclampsia via downregulation

of endothelial nitric oxide synthase

Suji Kim¹, Wonjin Park¹, Minsik Park¹, Taesam Kim¹, Kwon-Soo Ha¹, Young-Guen Kwon³, Young-Myeong Kim¹˙²˙*

¹Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon 24341,

Republic of Korea, ²Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon 24341,
Republic of Korea, ³College of Life Science and Biotechnology, Yonsei University, Seoul 120-752, Republic of Korea

Inflammatory cytokines, including TNF-α, were elevated in patients with cardiovascular diseases and are also

considered as crucial factors in the pathogenesis of preeclampsia; however, the underlying pathogenic mechanism
has not been clearly elucidated. The present study provides novel evidence that TNF-α leads to endothelial

dysfunction associated with hypertension and vascular remodeling in preeclampsia through downregulation of
eNOS by NF-kappaB-dependent biogenesis of miR-31-5p, which targets eNOS mRNA. The treatment of human

endothelial cells with TNF-α or miR-31-5p mimic decreased eNOS mRNA stability without affecting eNOS promoter
activity, resulting in inhibition of eNOS expression and NO/cGMP production. Moreover, TNF-α and miR-31-5p

mimic evoked endothelial dysfunction associated with defects in angiogenesis, trophoblastic invasion, and
vasorelaxation in an ex vivo cultured model of human placental arterial vessels, which are typical features of

preeclampsia. These results suggest that NF-kappaB-responsive miR-31-5p elicits endothelial dysfunction,
hypertension, and vascular remodeling via post-transcriptional downregulation of eNOS and is a molecular risk

factor in the pathogenesis and development of preeclampsia.