Inhibitory effect of Samul-tang on retinal neovascularization in oxygen-induced retinopathy

BMC Complementary and Alternative Medicine

Junghyun Kim¹  Jin Sook Kim¹  Eun Jin Sohn¹  Kyuhyung Jo¹  Chan-Sik Kim¹  Yun Mi Lee¹ 

[1] Korean Medicine-Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseongdaero, Yuseong-gu, Daejeon 305-811, South Korea

关键词: Oxygen-induced retinopathy;    Vascular endothelial growth factor;    Chemokine (C-X-C motif) receptor 4;    Stromal cell-derived factor 1;    Retinal neovascularization;   

Others  :  1222557
DOI  :  10.1186/s12906-015-0800-7

 received in 2015-02-05, accepted in 2015-08-03,  发布年份 2015

【 摘 要 】

Background

Retinal neovascularization is a common cause of vision loss in proliferative diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration. Samul-tang (SMT) is a widely used traditional herbal medicine in East Asia and is also known as Shimotsu-to in Japanese and Si-Wu decoction in Chinese. This study was designed to evaluate the inhibitory effect of SMT on retinal pathogenic angiogenesis in a mouse model of oxygen-induced retinopathy (OIR).

Method

The mice were exposed to a 75 % concentration of oxygen for five days, starting on postnatal day 7 (P7-P12). The mice were then exposed to room air and were intraperitoneally injected with SMT (10 mg/kg or 50 mg/kg) once per day for five days (P12-P16). On P17, we measured retinal neovascularization and evaluated both the expression of angiogenesis-related proteins and changes in the gene expression level in the mRNA.

Results

SMT reduced the area of the central retina and reduced retinal neovascularization in OIR mice. The protein array revealed that SMT reduced the level of SDF-1 protein expression. Quantitative real-time PCR revealed that the HIF-1α, SDF-1, CXCR4 and VEGF mRNA levels in the retinas of OIR mice were elevated compared with those of normal control mice. However, SMT decreased the levels of HIF-1α, SDF-1, CXCR4 and VEGF mRNA in OIR mice.

Conclusion

We are the first to elucidate that SMT inhibits the retinal pathogenic angiogenesis induced by ischemic retinopathy in OIR mice. SMT significantly inhibited retinal neovascularization by downregulating HIF-1α, SDF-1, CXCR4 and VEGF. Based on the results of our study, SMT could be a useful herbal medicine for treating ischemic retinopathy.

【 授权许可】

   
2015 Lee et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

【 参考文献 】

• [1]Campochiaro PA. Ocular neovascularization. J Mol Med (Berl). 2013; 91(3):311-321.
• [2]Wang W, Li Z, Sato T, Oshima Y. Tenomodulin inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy. Int J Mol Sci. 2012; 13(11):15373-15386.
• [3]Risau W. Mechanisms of angiogenesis. Nature. 1997; 386(6626):671-674.
• [4]Gariano RF, Gardner TW. Retinal angiogenesis in development and disease. Nature. 2005; 438(7070):960-966.
• [5]Tomao F, Papa A, Rossi L, Zaccarelli E, Caruso D, Zoratto F et al.. Angiogenesis and antiangiogenic agents in cervical cancer. Onco Targets Ther. 2014; 7:2237-2248.
• [6]Agrawal S, Joshi M, Christoforidis JB. Vitreous inflammation associated with intravitreal anti-VEGF pharmacotherapy. Mediators Inflamm. 2013; 2013:943409.
• [7]Zhang SX, Ma JX. Ocular neovascularization: implication of endogenous angiogenic inhibitors and potential therapy. Prog Retin Eye Res. 2007; 26(1):1-37.
• [8]Fong GH. Mechanisms of adaptive angiogenesis to tissue hypoxia. Angiogenesis. 2008; 11(2):121-140.
• [9]Liekens S, Schols D, Hatse S. CXCL12-CXCR4 axis in angiogenesis, metastasis and stem cell mobilization. Curr Pharm Des. 2010; 16(35):3903-3920.
• [10]De La Luz SM, Yang F, Narazaki M, Salvucci O, Davis D, Yarchoan R et al.. Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity. Blood. 2004; 103(7):2452-2459.
• [11]Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006; 107(5):1761-1767.
• [12]Cai X, Chen Z, Pan X, Xia L, Chen P, Yang Y et al.. Inhibition of angiogenesis, fibrosis and thrombosis by tetramethylpyrazine: mechanisms contributing to the SDF-1/CXCR4 axis. PLoS One. 2014; 9(2): Article ID e88176
• [13]Salcedo R, Wasserman K, Young HA, Grimm MC, Howard OM, Anver MR et al.. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol. 1999; 154(4):1125-1135.
• [14]Salcedo R, Oppenheim JJ, Salcedo R, Oppenheim JJ. Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation. 2003; 10(3–4):359-370.
• [15]Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S et al.. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell. 2006; 124(1):175-189.
• [16]Zhong Yi, Fang Ji, Xian Dai, Yan Jiu. Modern Study of the Medical Formula in Traditional Chinese Medicine Beijing Academy. Press, 1997.
• [17]Chang-Seob Seo HH, Da-Young J, Ho Young L, Shin H-K. Evaluation of the immune-stimulating activity of Samul-tang, a traditional Korean herbal medicine, standardized by HPLC-PDA. J Korean Or Med. 2011; 32(3):25-34.
• [18]Kojima S, Inaba K, Kobayashi S, Kimura M. Inhibitory effects of traditional Chinese medicine Shimotsu-to and its included crude fractions on adjuvant-induced chronic inflammation of mice. Biol Pharm Bull. 1996; 19(1):47-52.
• [19]Jin Yeul Ma YBY, Hye Kyung HA, Dae Sun H, Hyun Kyoo S. Subacute toxicity study on Samul-tang in SD rats. Korean J Or Physiol Patholog. 2008; 22(1):137-141.
• [20]Lee YM, Kim J, Jo K, Shin SD, Kim CS, Sohn EJ et al.. Ethyl pyruvate inhibits retinal pathogenic neovascularization by downregulating HMGB1 expression. J Diabetes Res. 2013; 2013:245271.
• [21]Yoo S-R, Jeong. Single oral dose toxicity evaluation of Samul-tang, a traditional herbal formula, in Crl:CD (SD) rats. J Korean Med. 2014; 35(2):28-33.
• [22]Connor KM, Krah NM, Dennison RJ, Aderman CM, Chen J, Guerin KI et al.. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc. 2009; 4(11):1565-1573.
• [23]Smith LE, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R et al.. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci. 1994; 35(1):101-111.
• [24]Simpson DA, Murphy GM, Bhaduri T, Gardiner TA, Archer DB, Stitt AW. Expression of the VEGF gene family during retinal vaso-obliteration and hypoxia. Biochem Biophys Res Commun. 1999; 262(2):333-340.
• [25]Gengrinovitch S, Greenberg SM, Cohen T, Gitay-Goren H, Rockwell P, Maione TE, et al. Platelet factor-4 inhibits the mitogenic activity of VEGF121 and VEGF165 using several concurrent mechanisms. J Biol Chem. 1995;270(25):15059–65.
• [26]Abu El-Asrar AM, Nawaz MI, Kangave D, Siddiquei MM, Ola MS, Opdenakker G. Angiogenesis regulatory factors in the vitreous from patients with proliferative diabetic retinopathy. Acta Diabetol. 2013; 50(4):545-551.
• [27]Park SW, Kim JH, Kim KE, Jeong MH, Park H, Park B et al.. Beta-lapachone inhibits pathological retinal neovascularization in oxygen-induced retinopathy via regulation of HIF-1alpha. J Cell Mol Med. 2014; 18(5):875-884.
• [28]Villalvilla A, Moro M, Arruza L, Redondo S, Fernandez-Cruz A, Fernandez-Durango R. Circulating endothelial progenitor cells are reduced in rat oxygen-induced retinopathy despite a retinal SDF-1/CXCR4 and VEGF proangiogenic response. Life Sci. 2012; 91(7–8):264-270.
• [29]Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO. Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res. 2003; 22(1):1-29.
• [30]Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L et al.. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A. 1995; 92(23):10457-10461.
• [31]Mohamed Al-Shabrawey ME, Julian N, Amira O, Sylvia M, Amany T. Targeting neovascularization in ischemic retinopathy: recent advances. Expert Review of Ophthalmology. 2013; 8(3):267-286.
• [32]Yoshida T, Zhang H, Iwase T, Shen J, Semenza GL, Campochiaro PA. Digoxin inhibits retinal ischemia-induced HIF-1alpha expression and ocular neovascularization. FASEB J. 2010; 24(6):1759-1767.
• [33]Butler JM, Guthrie SM, Koc M, Afzal A, Caballero S, Brooks HL et al.. SDF-1 is both necessary and sufficient to promote proliferative retinopathy. J Clin Invest. 2005; 115(1):86-93.
• [34]Sonmez K, Drenser KA, Capone A, Trese MT. Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology. 2008; 115(6):1065-1070.
• [35]Lima e Silva R, Shen J, Hackett SF, Kachi S, Akiyama H, Kiuchi K et al.. The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization. FASEB J. 2007; 21(12):3219-3230.
• [36]Unoki N, Murakami T, Nishijima K, Ogino K, van Rooijen N, Yoshimura N. SDF-1/CXCR4 contributes to the activation of tip cells and microglia in retinal angiogenesis. Invest Ophthalmol Vis Sci. 2010; 51(7):3362-3371.
• [37]Nishigaki A, Okada H, Okamoto R, Sugiyama S, Miyazaki K, Yasuda K et al.. Concentrations of stromal cell-derived factor-1 and vascular endothelial growth factor in relation to the diameter of human follicles. Fertil Steril. 2011; 95(2):742-746.
• [38]Nishigaki A, Okada H, Okamoto R, Shimoi K, Miyashiro H, Yasuda K et al.. The concentration of human follicular fluid stromal cell-derived factor-1 is correlated with luteinization in follicles. Gynecol Endocrinol. 2013; 29(3):230-234.
• [39]Lee HJ, Lee EO, Lee JH, Lee KS, Kim KH, Kim SH et al.. In vivo anti-cancer activity of Korean Angelica gigas and its major pyranocoumarin decursin. Am J Chin Med. 2009; 37(1):127-142.
• [40]Jung MH, Lee SH, Ahn EM, Lee YM. Decursin and decursinol angelate inhibit VEGF-induced angiogenesis via suppression of the VEGFR-2-signaling pathway. Carcinogenesis. 2009;30(4):655–61.
• [41]Kwak DH, Kim JK, Kim JY, Jeong HY, Keum KS, Han SH, et al. Anti-angiogenic activities of Cnidium officinale Makino and Tabanus bovinus. J Ethnopharmacol. 2002;81(3):373–9.
• [42]Deng H, Yan C, Xiao T, Yuan D, Xu J. Total glucosides of Paeonia lactiflora Pall inhibit vascular endothelial growth factor-induced angiogenesis. J Ethnopharmacol. 2010; 127(3):781-785.
• [43]Wang YB, Liu YF, Lu XT, Yan FF, Wang B, Bai WW et al.. Rehmannia glutinosa extract activates endothelial progenitor cells in a rat model of myocardial infarction through a SDF-1 alpha/CXCR4 cascade. PLoS One. 2013; 8(1): Article ID e54303