Hydroxysafflor Yellow A Blocks HIF-1 α Induction of NOX2 and Protects ZO-1 Protein in Cerebral Microvascular Endothelium
Zonula occludens-1 (ZO-1) is a tight junction protein in the cerebrovascular endothelium, responsible for blood-brain barrier function. Hydroxysafflor yellow A (HSYA) is a major ingredient of safflower ( L.) with antioxidative activity. This study investigated whether HSYA protected ZO-1 by targetin...
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Published in | Antioxidants Vol. 11; no. 4; p. 728 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
MDPI AG
07.04.2022
MDPI |
Subjects | |
Online Access | Get full text |
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Summary: | Zonula occludens-1 (ZO-1) is a tight junction protein in the cerebrovascular endothelium, responsible for blood-brain barrier function. Hydroxysafflor yellow A (HSYA) is a major ingredient of safflower (
L.) with antioxidative activity. This study investigated whether HSYA protected ZO-1 by targeting ROS-generating NADPH oxidases (NOXs). HSYA administration reduced cerebral vascular leakage with ZO-1 protection in mice after photothrombotic stroke, largely due to suppression of ROS-associated inflammation. In LPS-stimulated brain microvascular endothelial cells, HSYA increased the ratio of NAD
/NADH to restore Sirt1 induction, which bound to Von Hippel-Lindau to promote HIF-1
degradation. NOX2 was the predominant isoform of NOXs in endothelial cells and HIF-1
transcriptionally upregulated p47phox and Nox2 subunits for the assembly of the NOX2 complex, but the signaling cascades were blocked by HSYA via HIF-1
inactivation. When oxidate stress impaired ZO-1 protein, HSYA attenuated carbonyl modification and prevented ZO-1 protein from 20S proteasomal degradation, eventually protecting endothelial integrity. In microvascular ZO-1 deficient mice, we further confirmed that HSYA protected cerebrovascular integrity and attenuated ischemic injury in a manner that was dependent on ZO-1 protection. HSYA blocked HIF-1
/NOX2 signaling cascades to protect ZO-1 stability, suggestive of a potential therapeutic strategy against ischemic brain injury. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. |
ISSN: | 2076-3921 2076-3921 |
DOI: | 10.3390/antiox11040728 |