Research Papers:

Safflor yellow B reduces hypoxia-mediated vasoconstriction by regulating endothelial micro ribonucleic acid/nitric oxide synthase signaling

Chaoyun Wang _, Ying Yang, Miao Li, Xin Liu, Qiaoyun Wang, Wenyu Xin, Hongliu Sun and Qingyin Zheng

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Oncotarget. 2017; 8:93551-93566. https://doi.org/10.18632/oncotarget.20133

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Chaoyun Wang1, Ying Yang2, Miao Li2, Xin Liu2, Qiaoyun Wang2, Wenyu Xin2, Hongliu Sun2 and Qingyin Zheng3

1School of Enology, Binzhou Medical University, Yantai 264003, P.R. China

2School of Pharmacy, Binzhou Medical University, Yantai 264003, P.R. China

3Department of Otolaryngology-Head and Neck Surgery, Case Western Reserve University, Cleveland, OH 44106, USA

Correspondence to:

Chaoyun Wang, email: [email protected]

Keywords: HIF-1α, hypoxia, miR-199a, miR-138, NO synthase

Received: May 09, 2017     Accepted: July 12, 2017     Published: August 10, 2017


Hypoxia-induced generation of vasoconstrictors reduces cerebral blood flow (CBF) while nitric oxide (NO) synthase (NOS) and microRNAs (miRNA) in endothelial cells (ECs) suppress vasoconstriction. Safflor yellow B (SYB), a natural plant compound, previously attenuated angiotensin II-mediated injury of ECs and maintained endothelial function. This study investigated the putative involvement of NOS and miRNAs in SYB-mediated resistance to hypoxia-induced vasoconstriction. In vivo, chronic hypoxia was induced in rats, and SYB was administered intravenously. In vitro, rat primary aortic ECs were cultured under oxygen and glucose deprivation. After treatment with anti-microR-199a, as well as the NOS inhibitor, N(G)-nitro-L-arginine methyl ester, SYB, or both, cell viability, NO and peroxynitrite (ONOO-) levels, NOS expression, and miRNA levels were evaluated. SYB significantly alleviated hypoxia-mediated vasoconstriction and increased CBF endothelium-dependently. SYB upregulated miR-199a, increased EC viability, decreased endothelin-1 (ET-1) levels, inhibited protein kinase C (PKC) activity, and suppressed hypoxia inducible factor-1α (HIF-1α) expression. Furthermore, the SYB-mediated reduction of inducible NOS reduced ONOO- levels. In addition, SYB downregulated miR-138 and, thereby, enhanced S100A1 and endothelial NOS activity. Hypoxia-mediated regulation of miR-138 and miR-199a inhibited endothelial NOS expression and activation, which triggered ET-1 release and vasoconstriction. Therefore, SYB treatment reduced hypoxia-induced vasoconstriction through miR-199a/endothelial NOS signaling.

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