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Mechanism Study of the Protective Effects of Sodium Tanshinone IIA Sulfonate Against Atorvastatin-Induced Cerebral Hemorrhage in Zebrafish: Transcriptome Analysis
Zhou,Zhong Yan1,2; Zhao,Wai Rong1; Xiao,Ying1; Zhang,Jing1; Tang,Jing Yi1; Lee,Simon Ming Yuen2
2020-10-02
Source PublicationFrontiers in Pharmacology
ISSN1663-9812
Volume11
Abstract

Hemorrhage stroke is a severe vascular disease of the brain with a high mortality rate in humans. Salvia miltiorrhiza Bunge (Danshen) is a well-known Chinese Materia Medica for treating cerebral vascular and cardiovascular diseases in traditional Chinese medicine. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, which is the main active ingredient of Danshen. In our previous study, we established a zebrafish model of cerebral hemorrhage and found that STS dramatically decreased both the hemorrhage rate and hemorrhage area, although the underlying mechanism was not fully elucidated. We conducted a transcriptome analysis of the protective effect of STS against atorvastatin (Ator)-induced cerebral hemorrhage in zebrafish using RNA-seq technology. RNA-seq revealed 207 DEGs between the Ator-treated group and control group; the expression levels of 53 DEGs between the Ator-treated group and control group were reversed between the STS + Ator-treated group and Ator-treated group. GO enrichment analysis indicated that these 53 DEGs encode proteins with roles in hemoglobin complexes, oxygen carrier activity and oxygen binding, etc. KEGG analysis suggested that these 53 DEGs were most enriched in three items, namely, porphyrin and chlorophyll metabolism, ferroptosis, and the HIF-1 signaling pathway. The PPI network analysis identified 12 hub genes, and we further verified that Ator elevated the mRNA expression levels of hemoglobin (hbae1.3, hbae3, hbae5, hbbe2, and hbbe3), carbonic anhydrase (cahz), HIF-1 (hif1al2) and Na+/H+ exchanger (slc4a1a and slc9a1) genes, while STS significantly suppressed these genes. In addition, we found that pharmacological inhibition of PI3K/Akt, MAPKs, and mTOR signaling pathways by specific inhibitors partially attenuated the protective effect of STS against Ator-induced cerebral hemorrhage in zebrafish, regardless of mTOR inhibition. We concluded that hemoglobin, carbonic anhydrase, Na+/H+ exchanger and HIF-1 genes might be potential biomarkers of Ator-induced cerebral hemorrhage in zebrafish, as well as pharmacological targets of STS. Moreover, HIF-1 and its regulators, i.e., the PI3K/Akt and MAPK signaling pathways, were involved in the protective effect of STS against Ator-induced cerebral hemorrhage. This study also provided evidence of biomarkers involved in hemorrhage stroke and improved understanding of the effects of HMG-COA reductase inhibition on vascular permeability and cerebral hemorrhage.

KeywordAtorvastatin Carbonic Anhydrase Cerebral Hemorrhage Hemoglobin Hypoxia-inducible Factor 1 na+/h+ Exchanger Sodium Tanshinone Iia Sulfonate Traditional Chinese Medicine
DOI10.3389/fphar.2020.551745
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000577985600001
Scopus ID2-s2.0-85092898864
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Cited Times [WOS]:6   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorLee,Simon Ming Yuen
Affiliation1.Department of Cardiovascular Research Laboratory,Longhua Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai,China
2.State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macau,Macao
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Zhou,Zhong Yan,Zhao,Wai Rong,Xiao,Ying,et al. Mechanism Study of the Protective Effects of Sodium Tanshinone IIA Sulfonate Against Atorvastatin-Induced Cerebral Hemorrhage in Zebrafish: Transcriptome Analysis[J]. Frontiers in Pharmacology,2020,11.
APA Zhou,Zhong Yan,Zhao,Wai Rong,Xiao,Ying,Zhang,Jing,Tang,Jing Yi,&Lee,Simon Ming Yuen.(2020).Mechanism Study of the Protective Effects of Sodium Tanshinone IIA Sulfonate Against Atorvastatin-Induced Cerebral Hemorrhage in Zebrafish: Transcriptome Analysis.Frontiers in Pharmacology,11.
MLA Zhou,Zhong Yan,et al."Mechanism Study of the Protective Effects of Sodium Tanshinone IIA Sulfonate Against Atorvastatin-Induced Cerebral Hemorrhage in Zebrafish: Transcriptome Analysis".Frontiers in Pharmacology 11(2020).
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