Abstract
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.
Highlights
The nitric oxide (NO) generated and released by endothelial NO synthase in endothelial cells (ECs) exerts multiple beneficial effects on vessels and plays a critical role in maintaining cardiovascular homeostasis [1]
High NO levels, which are generated by the activation of inducible NOS (iNOS), subsequently promoting the production of the reactive oxygen species (ROS) peroxynitrite (ONOO-), which causes apoptosis and cell injury [1,2,3]
High NO levels are generated by iNOS in response to bacterial components and proinflammatory cytokines and are essential for immune functions by stimulating HIF-1 activity and increasing ONOO- generation [1, 3]
Summary
The nitric oxide (NO) generated and released by endothelial NO synthase (eNOS) in endothelial cells (ECs) exerts multiple beneficial effects on vessels and plays a critical role in maintaining cardiovascular homeostasis [1]. NO is a scavenger that effectively counteracts hypoxiamediated increases in reactive oxygen species (ROS) levels [2, 3]. Previous studies have shown that hypoxia can cause endothelial dysfunction, thereby promoting vasoconstriction and thrombosis, which reduces blood flow [6, 7]. These effects occur via downregulation of eNOS gene expression and inhibition of NO generation in ECs [6, 7]. Hypoxia/ ischemia aggravates the vascular response to ET-1, which increases cerebral vasoconstriction and decreases the cerebral blood flow (CBF) [9, 10].
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