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Sodium tanshinone IIA sulfonate promotes endothelial integrity via regulating VE-cadherin dynamics and RhoA/ROCK-mediated cellular contractility and prevents atorvastatin-induced intracerebral hemorrhage in zebrafish
Zhou, Zhong-Yan1,2; Huang, Bin1; Li, Shang1; Huang, Xiao-Hui1; Tang, Jing-Yi3; Kwan, Yiu Wa3; Hoi, Pui Man1; Lee, Simon Ming-Yuen1
2018-07
Source PublicationTOXICOLOGY AND APPLIED PHARMACOLOGY
ISSN0041-008X
Volume350Pages:32-42
Abstract

Impaired vascular integrity leads to serious cerebral vascular diseases such as intracerebral hemorrhage (ICH). In addition, high-dose statin therapy is suggested to cause increased ICH risk due to unclear effects of general inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) on the vascular system. Here we evaluated the protective effects of sodium tanshinone IIA sulfonate (STS), which has high efficacy and safety in clinical studies of ischemic stroke, by using atorvastatin (Ator) induced ICH zebrafish embryos and human umbilical vein endothelial cells (HUVECs). By using double transgenic Tg(flila:EGFP)yl & Tg(gatala:dsRed)sd2 zebrafish, we demonstrated that STS effectively reduced the occurrence and area of hemorrhage induced by Ator in zebrafish and restored impairment in motor function. We further demonstrated that Ator-induced disruption in VE-cadherin (VEC) containing cell-cell adherens junctions (AJs) in HUVECs by enhancing Src induced VEC internalization and RhoA/ROCK-mediated cellular contraction. STS inhibited Ator-induced Src activation and subsequent VEC internalization and actin depolymerization near cell borders, reducing lesions between neighboring cells and increasing barrier functions. STS also inhibited the Ator-induced RhoA/ROCK-mediated cellular contraction by regulating downstream LIMK/cofilin and MYPT1/MLC phosphatase signaling. These results showed that STS significantly promoted the stability of cell junctions and vascular integrity. Moreover, we observed that regulations of both Src and RhoA/ROCK are required for the maintenance of vascular integrity, and Src inhibitor (PP2) or ROCK inhibitors (fasudil and H1152) alone could not reduce the occurrence Ator-induced ICH. Taken together, we investigated the underlying mechanisms of Ator-induced endothelial instability, and provided scientific evidences of STS as potential ICH therapeutics by promoting vascular integrity.

KeywordSodium Tanshinone Iia Sulfonate Salvia Miltiorrhiza Hemorrhagic Stroke Atorvastatin Rock
DOI10.1016/j.taap.2018.04.037
URLView the original
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy ; Toxicology
WOS SubjectPharmacology & Pharmacy ; Toxicology
WOS IDWOS:000434494200004
PublisherACADEMIC PRESS INC ELSEVIER SCIENCE
The Source to ArticleWOS
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Cited Times [WOS]:5   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
2.Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
3.School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Zhou, Zhong-Yan,Huang, Bin,Li, Shang,et al. Sodium tanshinone IIA sulfonate promotes endothelial integrity via regulating VE-cadherin dynamics and RhoA/ROCK-mediated cellular contractility and prevents atorvastatin-induced intracerebral hemorrhage in zebrafish[J]. TOXICOLOGY AND APPLIED PHARMACOLOGY,2018,350:32-42.
APA Zhou, Zhong-Yan.,Huang, Bin.,Li, Shang.,Huang, Xiao-Hui.,Tang, Jing-Yi.,...&Lee, Simon Ming-Yuen.(2018).Sodium tanshinone IIA sulfonate promotes endothelial integrity via regulating VE-cadherin dynamics and RhoA/ROCK-mediated cellular contractility and prevents atorvastatin-induced intracerebral hemorrhage in zebrafish.TOXICOLOGY AND APPLIED PHARMACOLOGY,350,32-42.
MLA Zhou, Zhong-Yan,et al."Sodium tanshinone IIA sulfonate promotes endothelial integrity via regulating VE-cadherin dynamics and RhoA/ROCK-mediated cellular contractility and prevents atorvastatin-induced intracerebral hemorrhage in zebrafish".TOXICOLOGY AND APPLIED PHARMACOLOGY 350(2018):32-42.
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