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

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

  • Antioxidants (Basel). 2022 Apr 7;11(4):728. doi: 10.3390/antiox11040728.
Yi Li 1 Xiao-Tian Liu 1 Pei-Lin Zhang 1 Yu-Chen Li 1 Meng-Ru Sun 1 Yi-Tao Wang 2 Sheng-Peng Wang 2 Hua Yang 1 Bao-Lin Liu 1 Mei Wang 3 Wen Gao 1 Ping Li 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China.
  • 2 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China.
  • 3 Leiden University-European Center for Chinese Medicine and Natural Compounds, Institute of Biology/SU BioMedicine, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands.
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.

Keywords

HIF-1α; NOX2; ZO-1; cerebral microvascular endothelium; hydroxysafflor yellow A.

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