Dihydroartemisinin Ameliorates Cerebral I/R Injury in Rats Via Regulating VWF and Autophagy-mediated SIRT1/FOXO1 Pathway

Overview

Journal Open Med (Wars)

Specialty General Medicine

Date 2023 Jul 7

PMID 37415610

Authors

Qi Duan

Junxia Wu

Affiliations

Soon will be listed here.

Abstract

Dihydroartemisinin (DHA) has been found to inhibit the expression of von Willebrand factor (VWF), a marker of endothelial cell injury, but its mechanism in cerebral ischemia/reperfusion (I/R) injury remains obscure. In this study, I/R model was constructed through middle cerebral artery occlusion (MCAO) in rats, followed by DHA administration. The effect of DHA on rat cerebral I/R injury was investigated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin and eosin staining, TUNEL staining, and Western blot. Brain microvascular endothelial cells (BMVECs) isolated from newborn rats were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R), and then treated with DHA. The results showed that MCAO treatment induced infarction, nerve cell apoptosis, and brain tissue impairment in rats, which was mitigated by DHA. OGD/R inhibited viability and accelerated apoptosis of BMVECs, which was alleviated by DHA. I/R procedures or OGD/R up-regulated expressions of VWF, ATG7, Beclin1, and LC3-II/LC3-I ratio, while down-regulating Occludin, Claudin-5, ZO-1, P62, SIRT1, and FOXO1 expressions and ; however, these effects of I/R procedures or OGD/R were offset by DHA. VWF overexpression reversed the above effects of DHA on OGD/R-induced BMVECs. In summary, DHA ameliorates cerebral I/R injury in rats by reducing VWF level and activating autophagy-mediated SIRT1/FOXO1 signaling pathway.

Citing Articles

Esketamine at a Clinical Dose Attenuates Cerebral Ischemia/Reperfusion Injury by Inhibiting AKT Signaling Pathway to Facilitate Microglia M2 Polarization and Autophagy.

Gao Y, Li L, Zhao F, Cheng Y, Jin M, Xue F Drug Des Devel Ther. 2025; 19:369-387.

PMID: 39867864 PMC: 11760763. DOI: 10.2147/DDDT.S504179.

Protective Role of Oxycodone in Myocardial Oxidative Stress and Mitochondrial Dysfunction Induced by Ischemia-Reperfusion.

Jiang Y, He H, Jia X J Biochem Mol Toxicol. 2025; 39(2):e70151.

PMID: 39865943 PMC: 11837462. DOI: 10.1002/jbt.70151.

From Microcirculation to Aging-Related Diseases: A Focus on Endothelial SIRT1.

Law M, Wang P, Zhou Z, Wang Y Pharmaceuticals (Basel). 2024; 17(11).

PMID: 39598406 PMC: 11597311. DOI: 10.3390/ph17111495.

References

Shi C, Jin J, Wang X, Song T, Li G, Li K . Sevoflurane attenuates brain damage through inhibiting autophagy and apoptosis in cerebral ischemia‑reperfusion rats. Mol Med Rep. 2019; 21(1):123-130. PMC: 6896401. DOI: 10.3892/mmr.2019.10832. View

Haybar H, Khodadi E, Kavianpour M, Saki N . Mutations and Common Polymorphisms in ADAMTS13 and vWF Genes Responsible for Increasing Risk of Thrombosis. Cardiovasc Hematol Disord Drug Targets. 2018; 18(3):176-181. DOI: 10.2174/1871529X18666180419102214. View

Ilett K, Ethell B, Maggs J, Davis T, Batty K, Burchell B . Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos. 2002; 30(9):1005-12. DOI: 10.1124/dmd.30.9.1005. View

Wu Q, Hu Y, Jiang M, Wang F, Gong G . Effect of Autophagy Regulated by Sirt1/FoxO1 Pathway on the Release of Factors Promoting Thrombosis from Vascular Endothelial Cells. Int J Mol Sci. 2019; 20(17). PMC: 6747322. DOI: 10.3390/ijms20174132. View

Mizushima N, Yoshimori T, Levine B . Methods in mammalian autophagy research. Cell. 2010; 140(3):313-26. PMC: 2852113. DOI: 10.1016/j.cell.2010.01.028. View

Zuo G, Zhang D, Mu R, Shen H, Li X, Wang Z . Resolvin D2 protects against cerebral ischemia/reperfusion injury in rats. Mol Brain. 2018; 11(1):9. PMC: 5812187. DOI: 10.1186/s13041-018-0351-1. View

Hu X, De Silva T, Chen J, Faraci F . Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke. Circ Res. 2017; 120(3):449-471. PMC: 5313039. DOI: 10.1161/CIRCRESAHA.116.308427. View

Kirchoff-Torres K, Bakradze E . Cerebral Hyperperfusion Syndrome After Carotid Revascularization and Acute Ischemic Stroke. Curr Pain Headache Rep. 2018; 22(4):24. DOI: 10.1007/s11916-018-0678-4. View

Zhou F, Wang L, Liu P, Hu W, Zhu X, Shen H . Puerarin protects brain tissue against cerebral ischemia/reperfusion injury by inhibiting the inflammatory response. Neural Regen Res. 2015; 9(23):2074-80. PMC: 4316472. DOI: 10.4103/1673-5374.147934. View

10.

Lip G, Blann A . von Willebrand factor and its relevance to cardiovascular disorders. Br Heart J. 1995; 74(6):580-3. PMC: 484109. DOI: 10.1136/hrt.74.6.580. View

11.

Wang K, Zhang W, Liu J, Cui Y, Cui J . Piceatannol protects against cerebral ischemia/reperfusion‑induced apoptosis and oxidative stress via the Sirt1/FoxO1 signaling pathway. Mol Med Rep. 2020; 22(6):5399-5411. PMC: 7647030. DOI: 10.3892/mmr.2020.11618. View

12.

Shao Z, Dou S, Zhu J, Wang H, Wang C, Cheng B . Apelin-13 inhibits apoptosis and excessive autophagy in cerebral ischemia/reperfusion injury. Neural Regen Res. 2020; 16(6):1044-1051. PMC: 8224111. DOI: 10.4103/1673-5374.300725. View

13.

Zhang F, Li Z, Xu X, Hu Y, Yao J, Xu W . Protective effects of icariin-mediated SIRT1/FOXO3 signaling pathway on intestinal ischemia/reperfusion-induced acute lung injury. Mol Med Rep. 2014; 11(1):269-76. DOI: 10.3892/mmr.2014.2679. View

14.

Huang L, Chen C, Zhang X, Li X, Chen Z, Yang C . Neuroprotective Effect of Curcumin Against Cerebral Ischemia-Reperfusion Via Mediating Autophagy and Inflammation. J Mol Neurosci. 2017; 64(1):129-139. DOI: 10.1007/s12031-017-1006-x. View

15.

Yang D, Qiu J, Zhou H, Yu Y, Zhou D, Xu Y . Dihydroartemisinin alleviates oxidative stress in bleomycin-induced pulmonary fibrosis. Life Sci. 2018; 205:176-183. DOI: 10.1016/j.lfs.2018.05.022. View

16.

Yang D, Yuan W, Lv C, Li N, Liu T, Wang L . Dihydroartemisinin supresses inflammation and fibrosis in bleomycine-induced pulmonary fibrosis in rats. Int J Clin Exp Pathol. 2015; 8(2):1270-81. PMC: 4396330. View

17.

Liu J, Ren Y, Hou Y, Zhang C, Wang B, Li X . Dihydroartemisinin Induces Endothelial Cell Autophagy through Suppression of the Akt/mTOR Pathway. J Cancer. 2019; 10(24):6057-6064. PMC: 6856569. DOI: 10.7150/jca.33704. View

18.

Urisono Y, Sakata A, Matsui H, Kasuda S, Ono S, Yoshimoto K . Von Willebrand Factor Aggravates Hepatic Ischemia-Reperfusion Injury by Promoting Neutrophil Recruitment in Mice. Thromb Haemost. 2018; 118(4):700-708. DOI: 10.1055/s-0038-1636529. View

19.

Pozzi N, Lancellotti S, De Cristofaro R, De Filippis V . Modeling ADAMTS13-von Willebrand factor interaction: Implications for oxidative stress-related cardiovascular diseases and type 2A von Willebrand disease. Biophys Chem. 2011; 160(1):1-11. DOI: 10.1016/j.bpc.2011.07.007. View

20.

Keep R, Andjelkovic A, Xiang J, Stamatovic S, Antonetti D, Hua Y . Brain endothelial cell junctions after cerebral hemorrhage: Changes, mechanisms and therapeutic targets. J Cereb Blood Flow Metab. 2018; 38(8):1255-1275. PMC: 6092767. DOI: 10.1177/0271678X18774666. View