Sodium tanshinone IIA sulfonate ameliorates cerebral ischemic injury through regulation of angiogenesis

Xu,Jiazhen; Zhang,Pei; Chen,Yao; Xu,Yulan; Luan,Pengwei; Zhu,Yuying; Zhang,Jiange

doi:10.3892/etm.2021.10556

Sodium tanshinone IIA sulfonate ameliorates cerebral ischemic injury through regulation of angiogenesis

Authors:
- Jiazhen Xu
- Pei Zhang
- Yao Chen
- Yulan Xu
- Pengwei Luan
- Yuying Zhu
- Jiange Zhang
View Affiliations

Affiliations: Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
Published online on: August 4, 2021 https://doi.org/10.3892/etm.2021.10556
Article Number: 1122
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Vascular remodeling and neuroprotection are two major adaptable methods for treating ischemic stroke. Edaravone is a protective agent for the treatment of stroke and was used as a positive control in the present study. Sodium tanshinone IIA sulfonate (STS) has demonstrated therapeutic clinical effects in cerebral infarction in China, while its mechanisms of action in ischemic stroke have remained elusive. The angiogenesis and neuroprotective effects of STS were evaluated in a rat model induced by middle cerebral artery occlusion and 3 days of reperfusion. When used at the same dose, the magnitude of the therapeutic effect of STS was similar to that of edaravone in terms of decreased blood‑brain barrier damage as indicated by reduced Evans blue leakage, improved neurological deficits, alleviated cerebral edema and inhibition of histopathological changes caused by ischemia/reperfusion. The TUNEL assay demonstrated that the ability of STS to inhibit neuronal apoptosis was equivalent to that of edaravone. Immunofluorescence detection of CD31 and α‑smooth muscle actin indicated that the vascular density was significantly reduced in the vehicle group compared with that in the sham operation group, STS increased the microvessel density in the ischemic area. Furthermore, in the vehicle group the protein expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR) as determined by fluorescence microscopy and immunohistochemistry was significantly reduced compared with that in the sham group. However, STS promoted their expression compared to the vehicle group respectively, and increaed the mRNA expression of VEGF, VEGFR, CD31 and angiopoietin‑1 as determined by reverse transcription‑quantitative PCR, but these changes were not significant or not present for edaravone apart from Ang‑1. In conclusion, STS protected against ischemic brain injury by promoting angiogenesis in ischemic areas and inhibiting neuronal apoptosis. These results provide a potential treatment for stroke recovery.

View Figures

View References

1	Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, De Ferranti SD, Floyd JS, Fornage M, Gillespie C, et al: Heart disease and stroke statistics-2017 update: A report from the American heart association. Circulation. 135:e146–e603. 2017.PubMed/NCBI View Article : Google Scholar
2	Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, et al: Heart disease and stroke statistics-2018 update: A report from the American heart association. Circulation. 137:e67–e492. 2018.PubMed/NCBI View Article : Google Scholar
3	Winstein CJ, Stein J, Arena R, Bates BE, Cherney LR, Cramer SC, Deruyter F, Eng JJ, Fisher BE, Harvey RL, et al: Guidelines for adult stroke rehabilitation and recovery: A guideline for healthcare professionals from the American heart association/American stroke association. Stroke. 47:e98–e169. 2016.PubMed/NCBI View Article : Google Scholar
4	Shang Q, Xu H and Huang L: Tanshinone IIA: A promising natural cardioprotective agent. Evid Based Complement Alternat Med. 2012(716459)2012.PubMed/NCBI View Article : Google Scholar
5	Shang QH, Wang H, Li SM and Xu H: The effect of sodium tanshinone IIA sulfate and simvastatin on elevated serum levels of inflammatory markers in patients with coronary heart disease: A study protocol for a randomized controlled trial. Evid Based Complement Alternat Med. 2013(756519)2013.PubMed/NCBI View Article : Google Scholar
6	Tang J, Zhu C, Li ZH, Liu XY, Sun SK, Zhang T, Luo ZJ, Zhang H and Li WY: Inhibition of the spinal astrocytic JNK/MCP-1 pathway activation correlates with the analgesic effects of tanshinone IIA sulfonate in neuropathic pain. J Neuroinflamm. 12(57)2015.PubMed/NCBI View Article : Google Scholar
7	Zhang H, Long M, Wu Z, Han X and Yu Y: Sodium tanshinone IIA silate as an add-on therapy in patients with unstable angina pectoris. J Thorac Dis. 6:1794–1799. 2014.PubMed/NCBI View Article : Google Scholar
8	Zhao YP, Wang F, Jiang W, Liu J, Liu BL, Qi L and Zhou W: A mitochondrion-targeting tanshinone IIA derivative attenuates myocardial hypoxia reoxygenation injury through a SDH-dependent antioxidant mechanism. J Drug Target. 27:896–902. 2019.PubMed/NCBI View Article : Google Scholar
9	Hu Q, Wei B, Wei L, Hua K, Yu X, Li H and Ji H: Sodium tanshinone IIA sulfonate ameliorates ischemia-induced myocardial inflammation and lipid accumulation in beagle dogs through NLRP3 inflammasome. Int J Cardiol. 196:183–192. 2015.PubMed/NCBI View Article : Google Scholar
10	Xu W, Yang J and Wu LM: Cardioprotective effects of tanshinone IIA on myocardial ischemia injury in rats. Pharmazie. 64:332–336. 2009.PubMed/NCBI
11	Morton JS, Andersson IJ, Cheung P, Baker PN and Davidge ST: The vascular effects of sodium tanshinone IIA sulphonate in rodent and human pregnancy. PLoS One. 10(e0121897)2015.PubMed/NCBI View Article : Google Scholar
12	Ji B, Zhou F, Han L, Yang J, Fan H, Li S, Li J, Zhang X, Wang X and Chen X: Sodium tanshinone IIA sulfonate enhances effectiveness Rt-PA treatment in acute ischemic stroke patients associated with ameliorating blood-brain barrier damage. Transl Stroke Res. 8:334–340. 2017.PubMed/NCBI View Article : Google Scholar
13	Zhou ZY, Huang B, Li S, Huang XH, Tang JY, Kwan YW, Hoi PM and Lee SMY: 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. Toxicol Appl Pharmacol. 350:32–42. 2018.PubMed/NCBI View Article : Google Scholar
14	Li Z, Zhang S, Cao L, Li W, Ye YC, Shi ZX, Wang ZR, Sun LX, Wang JW, Jia LT and Wang W: Tanshinone IIA and Astragaloside IV promote the angiogenesis of mesenchymal stem cell-derived endothelial cell-like cells via upregulation of Cx37, Cx40 and Cx43. Exp Ther Med. 16:1847–1854. 2018.PubMed/NCBI View Article : Google Scholar
15	Garcia JH, Wagner S, Liu KF and Hu XJ: Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke. 26:627–635. 1995.PubMed/NCBI View Article : Google Scholar
16	Lo EH: A new penumbra: Transitioning from injury into repair after stroke. Nat Med. 14:497–500. 2008.PubMed/NCBI View Article : Google Scholar
17	Ma F, Morancho A, Montaner J and Rosell A: Endothelial progenitor cells and revascularization following stroke. Brain Res. 1623:150–159. 2015.PubMed/NCBI View Article : Google Scholar
18	Jiang Y, Li L, Ma J, Zhang L, Niu F, Feng T and Li C: Auricular vagus nerve stimulation promotes functional recovery and enhances the post-ischemic angiogenic response in an ischemia/reperfusion rat model. Neurochem Int. 97:73–82. 2016.PubMed/NCBI View Article : Google Scholar
19	Han L and Li J, Chen Y, Zhang M, Qian L, Chen Y, Wu Z, Xu Y and Li J: Human urinary kallidinogenase promotes angiogenesis and cerebral perfusion in experimental stroke. PLoS One. 10(e0134543)2015.PubMed/NCBI View Article : Google Scholar
20	Hui Z, Sha DJ, Wang SL, Li CS, Qian J, Wang JQ, Zhao Y, Zhang JH, Cheng HY, Yang H, et al: Panaxatriol saponins promotes angiogenesis and enhances cerebral perfusion after ischemic stroke in rats. BMC Complement Altern Med. 17(70)2017.PubMed/NCBI View Article : Google Scholar
21	Petcu EB, Smith RA, Miroiu RI and Opris MM: Angiogenesis in old-aged subjects after ischemic stroke: A cautionary note for investigators. J Angiogenes Res. 2(26)2010.PubMed/NCBI View Article : Google Scholar
22	Arai K, Jin G, Navaratna D and Lo EH: Brain angiogenesis in developmental and pathological processes: Neurovascular injury and angiogenic recovery after stroke. FEBS J. 276:4644–4652. 2009.PubMed/NCBI View Article : Google Scholar
23	Li W, Fraser JL, Yu SP, Zhu J, Jiang Y and Wei L: The role of VEGF/VEGFR2 signaling in peripheral stimulation-induced cerebral neurovascular regeneration after ischemic stroke in mice. Exp Brain Res. 214:503–513. 2011.PubMed/NCBI View Article : Google Scholar
24	Lee DH, Lee J, Jeon J, Kim KJ, Yun JH, Jeong HS, Lee EH, Koh YJ and Cho CH: Oleanolic acids inhibit vascular endothelial growth factor receptor 2 signaling in endothelial cells: Implication for anti-angiogenic therapy. Mol Cells. 41:771–780. 2018.PubMed/NCBI View Article : Google Scholar
25	Wise GE and Yao S: Expression of vascular endothelial growth factor in the dental follicle. Crit Rev Eukaryot Gene Expr. 13:173–180. 2003.PubMed/NCBI
26	Krum JM, Mani N and Rosenstein JM: Angiogenic and astroglial responses to vascular endothelial growth factor administration in adult rat brain. Neuroscience. 110:589–604. 2002.PubMed/NCBI View Article : Google Scholar
27	Melincovici CS, Boşca AB, Şuşman S, Mărginean M, Mihu C, Istrate M, Moldovan IM, Roman AL and Mihu CM: Vascular endothelial growth factor (VEGF)-key factor in normal and pathological angiogenesis. Rom J Morphol Embryol. 59:455–467. 2018.PubMed/NCBI
28	Wang Y, Jin K, Mao XO, Xie L, Banwait S, Marti HH and Greenberg DA: VEGF-overexpressing transgenic mice show enhanced post-ischemic neurogenesis and neuromigration. J Neurosci Res. 85:740–747. 2007.PubMed/NCBI View Article : Google Scholar
29	Asahara T, Chen D, Takahashi T, Fujikawa K, Kearney M, Magner M, Yancopoulos GD and Isner JM: Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ Res. 83:233–240. 1998.PubMed/NCBI View Article : Google Scholar
30	Wang L, Xiong X, Zhang X, Ye Y, Jian Z, Gao W and Gu L: Sodium tanshinone IIA sulfonate protects against cerebral ischemia-reperfusion injury by inhibiting autophagy and inflammation. Neuroscience. 441:46–57. 2020.PubMed/NCBI View Article : Google Scholar
31	Chen L, He W, Peng B, Yuan M, Wang N, Wang J, Lu W and Wang T: Sodium tanshinone IIA sulfonate improves post-ischemic angiogenesis in hyperglycemia. Biochem Biophys Res Commun. 520:580–585. 2019.PubMed/NCBI View Article : Google Scholar
32	Zhou Z, Wei X, Xiang J, Gao J, Wang L, You J, Cai Y and Cai D: Protection of erythropoietin against ischemic neurovascular unit injuries through the effects of connexin43. Biochem Biophys Res Commun. 458:656–662. 2015.PubMed/NCBI View Article : Google Scholar
33	Longa EZ, Weinstein P, Carlson S and Cummins R: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 20:84–91. 1989.PubMed/NCBI View Article : Google Scholar
34	Wang J, Zhang D, Fu X, Yu L, Lu Z, Gao Y, Liu X, Man J, Li S, Li N, et al: Carbon monoxide-releasing molecule-3 protects against ischemic stroke by suppressing neuroinflammation and alleviating blood-brain barrier disruption. J Neuroinflammation. 15(188)2018.PubMed/NCBI View Article : Google Scholar
35	Li D, Lang W, Zhou C, Wu C, Zhang F, Liu Q, Yang S and Hao J: Upregulation of microglial ZEB1 ameliorates brain damage after acute ischemic stroke. Cell Rep. 22:3574–3586. 2018.PubMed/NCBI View Article : Google Scholar
36	Gilmer LK, Roberts KN and Scheff SW: Efficacy of progesterone following a moderate unilateral cortical contusion injury. J Neurotrauma. 25:593–602. 2008.PubMed/NCBI View Article : Google Scholar
37	Luan P, Xu J, Ding X, Cui Q, Jiang L, Xu Y, Zhu Y, Li R, Lin G, Tian P and Zhang J: Neuroprotective effect of salvianolate on cerebral ischaemia-reperfusion injury in rats by inhibiting the caspase-3 signal pathway. Eur J Pharmacol. 872(172944)2020.PubMed/NCBI View Article : Google Scholar
38	Zhu Y, Yang L, Xu J, Yang X, Luan P, Cui Q, Zhang P, Wang F, Li R, Ding X, et al: Discovery of the anti-angiogenesis effect of eltrombopag in breast cancer through targeting of HuR protein. Acta Pharm Sin B. 10:1414–1425. 2020.PubMed/NCBI View Article : Google Scholar
39	Taguchi A, Soma T, Tanaka H, Kanda T, Nishimura H, Yoshikawa H, Tsukamoto Y, Iso H, Fujimori Y, Stern DM, et al: Administration of CD34⁺ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J Clin Invest. 114:330–338. 2004.PubMed/NCBI View Article : Google Scholar
40	Zhang ZG, Zhang L, Jiang Q, Zhang RL, Davies K, Powers C, Bruggen NV and Chopp M: VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest. 106:829–838. 2000.PubMed/NCBI View Article : Google Scholar
41	Zhou L, Zuo Z and Chow MS: Danshen: An overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol. 45:1345–1359. 2005.PubMed/NCBI View Article : Google Scholar
42	Chan P, Liu IM, Li YX, Yu WJ and Cheng JT: Antihypertension induced by tanshinone IIA isolated from the roots of Salvia miltiorrhiza. Evid Based Complement Alternat Med. 2011(392627)2011.PubMed/NCBI View Article : Google Scholar
43	Gong P, Zhang Z, Zou C, Tian Q, Chen X, Hong M, Liu X, Chen Q, Xu Z, Li M and Wang J: Hippo/YAP signaling pathway mitigates blood-brain barrier disruption after cerebral ischemia/reperfusion injury. Behav Brain Res. 356:8–17. 2019.PubMed/NCBI View Article : Google Scholar
44	Giraud M, Cho TH, Nighoghossian N, Maucort-Boulch D, Deiana G, Østergaard L, Baron JC, Fiehler J, Pedraza S, Derex L and Berthezène Y: Early blood brain barrier changes in acute ischemic stroke: A sequential MRI study. J Neuroimaging. 25:959–963. 2015.PubMed/NCBI View Article : Google Scholar
45	Navaratna D, Guo S, Arai K and Lo EH: Mechanisms and targets for angiogenic therapy after stroke. Cell Adh Migr. 3:216–223. 2009.PubMed/NCBI View Article : Google Scholar
46	Ampofo E, Schmitt BM, Menger MD and Laschke MW: Targeting the microcirculation by indole-3-carbinol and its main derivate 3,3,'-diindolylmethane: Effects on angiogenesis, thrombosis and inflammation. Mini Rev Med Chem. 18:962–968. 2018.PubMed/NCBI View Article : Google Scholar
47	Zhu W, Lv Q, Chen H, Wang Z and Zhong Q: Protective effect and mechanism of sodium tanshinone II A sulfonate on microcirculatory disturbance of small intestine in rats with sepsis. J Huazhong Univ Sci Technolog Med Sci. 31(441)2011.PubMed/NCBI View Article : Google Scholar
48	Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A and Greenberg DA: VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest. 111:1843–1851. 2003.PubMed/NCBI View Article : Google Scholar
49	Liu J, Wang Y, Akamatsu Y, Lee CC, Stetler RA, Lawton MT and Yang GY: Vascular remodeling after ischemic stroke: Mechanisms and therapeutic potentials. Prog Neurobiol. 115:138–156. 2014.PubMed/NCBI View Article : Google Scholar
50	Pedragosa J, Salas-Perdomo A, Gallizioli M, Cugota R, Miró-Mur F, Briansó F, Justicia C, Pérez-Asensio F, Marquez-Kisinousky L, Urra X, et al: CNS-border associated macrophages respond to acute ischemic stroke attracting granulocytes and promoting vascular leakage. Acta Neuropathol Commun. 6(76)2018.PubMed/NCBI View Article : Google Scholar