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Hydroxysafflor Yellow A Blocks HIF-1α Induction of NOX2 and Protects ZO-1 Protein in Cerebral Microvascular Endothelium

Authors :
Yi Li
Xiao-Tian Liu
Pei-Lin Zhang
Yu-Chen Li
Meng-Ru Sun
Yi-Tao Wang
Sheng-Peng Wang
Hua Yang
Bao-Lin Liu
Mei Wang
Wen Gao
Ping Li
Source :
Antioxidants, Vol 11, Iss 4, p 728 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

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 (Carthamus tinctorius 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-1αdegradation. NOX2 was the predominant isoform of NOXs in endothelial cells and HIF-1α transcriptionally upregulated p47phox and Nox2 subunits for the assembly of the NOX2 complex, but the signaling cascades were blocked by HSYA via HIF-1α 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-1α/NOX2 signaling cascades to protect ZO-1 stability, suggestive of a potential therapeutic strategy against ischemic brain injury.

Details

Language :
English
ISSN :
20763921
Volume :
11
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Antioxidants
Publication Type :
Academic Journal
Accession number :
edsdoj.0372d341945f44c4a3492fb89522408f
Document Type :
article
Full Text :
https://doi.org/10.3390/antiox11040728