Intraocular injection of KH902 alleviates retinal hypoxia in a mouse model of oxygen-induced retinopathy

Authors

  • Ning Yang Department of Ophthalmology, Renmin Hospital of Wuhan University, #238 Jiefang Road, Wuhan, 430060, China https://orcid.org/0000-0003-3036-0202
  • Xuejun He Department of Ophthalmology, Renmin Hospital of Wuhan University, #238 Jiefang Road, Wuhan, 430060, China
  • Ningzhi Zhang Department of Ophthalmology, Renmin Hospital of Wuhan University, #238 Jiefang Road, Wuhan, 430060, China
  • Yiqiao Xing Department of Ophthalmology, Renmin Hospital of Wuhan University, #238 Jiefang Road, Wuhan, 430060, China

DOI:

https://doi.org/10.2298/ABS210814038Y

Keywords:

retinal neovascularization, KH902, retinal hypoxia, retinopathy of prematurity, oxygen-induced retinopathy

Abstract

Paper description:

  • KH902 (conbercept) is a novel anti-angiogenic agent.
  • KH902 was injected intravitreally to analyze its effect on retinal hypoxia and neuroretinal structure in the oxygen-induced retinopathy (OIR) mouse model.
  • Intravitreal injection of KH902 inhibited the formation of retinal neovascularization in OIR at postnatal day (P17). Intravitreal injection of KH902 had a significant effect on remitting the retinal hypoxia both at P14 and P17. Intravitreal injection of KH902 did not damage the neuroretinal structure at P17 in OIR.
  • Intravitreal injection of KH902 should be safe and effective in restraining ocular angiogenesis and improving the retinal hypoxic condition.

Abstract: Inhibition of vascular endothelial growth factor (VEGF) has been widely applied in anti-neovascularization therapies. As a novel anti-VEGF agent, KH902 (conbercept) is designed to restrain pathological angiogenesis. However, the effects of KH902 on retinal hypoxia have not been well studied. In a mouse model of oxygen-induced retinopathy (OIR), we assessed retinal hypoxia at postnatal days 14 (P14) and P17, as well as retinal neovascularization (RNV) at P17. In addition, we evaluated the protein level of VEGF and galectin-1 (Gal-1). Changes of the neuroretinal structure were also examined. Our results indicated that KH902 could remit retinal hypoxia in OIR at P14 and P17, which was an exciting novel finding for KH902 function. Additionally, we confirmed that KH902 markedly reduces RNV. Our results indicated that administration of KH902 downregulated VEGF expression, as well as Gal-1. Damage of neuroretinal structure after KH902 injection was not observed, which was also an encouraging result. Our study suggests that KH902 plays a role in alleviating retinal hypoxia and that it could be used for the treatment of other neovascular ocular diseases.

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References

Hooglugt A, van der Stoel MM, Boon RA, Huveneers S. Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature. Front Oncol. 2020;10:612802.

http://doi.org/10.3389/fonc.2020.612802

Shi W, Xin Q, Yuan R, Yuan Y, Cong W, Chen K. Neovascularization: The Main Mechanism of MSCs in Ischemic Heart Disease Therapy. Front Cardiovasc Med. 2021;8:633300.

http://doi.org/10.3389/fcvm.2021.633300

Rodrigues M, Xin X, Jee K, Babapoor-Farrokhran S, Kashiwabuchi F, Ma T, Bhutto I, Hassan SJ, Daoud Y, Baranano D, et al. VEGF secreted by hypoxic Muller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy. Diabetes. 2013;62(11):3863-73.

http://doi.org/10.2337/db13-0014

Valikodath NG, Chiang MF, Chan RVP. Description and management of retinopathy of prematurity reactivation after intravitreal antivascular endothelial growth factor therapy. Curr Opin Ophthalmol. 2021;32(5):468-74.

http://doi.org/10.1097/ICU.0000000000000786

Ahmed SB, Higham A, Mulvihill A, Chan TKJ, Adams G, Patel CK. The UK practice of Anti-VEGF therapy for treatment of retinopathy of prematurity. Eye (London, England). 2021;35(9):2451-3.

http://doi.org/10.1038/s41433-021-01543-9

Jo DH, Kim S, Kim D, Kim JH, Jon S, Kim JH. VEGF-binding aptides and the inhibition of choroidal and retinal neovascularization. Biomaterials. 2014;35(9):3052-9.

http://doi.org/10.1016/j.biomaterials.2013.12.031

Avery RL, Pearlman J, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ, Wendel R, Patel A. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology. 2006;113(10):1695 e1-15.

http://doi.org/10.1016/j.ophtha.2006.05.064

Trichonas G, Kaiser PK. Aflibercept for the treatment of age-related macular degeneration. Ophthalmol Ther. 2013;2(2):89-98.

http://doi.org/10.1007/s40123-013-0015-2

Lai TY, Luk FO, Lee GK, Lam DS. Long-term outcome of intravitreal anti-vascular endothelial growth factor therapy with bevacizumab or ranibizumab as primary treatment for subfoveal myopic choroidal neovascularization. Eye (London, England). 2012;26(7):1004-11.

http://doi.org/10.1038/eye.2012.97

Mintz-Hittner HA. Intravitreal pegaptanib as adjunctive treatment for stage 3+ ROP shown to be effective in a prospective, randomized, controlled multicenter clinical trial. Eur J Ophthalmol. 2012;22(5):685-6.

http://doi.org/10.5301/ejo.5000176

Plyukhova AA, Budzinskaya MV, Starostin KM, Rejdak R, Bucolo C, Reibaldi M, Toro MD. Comparative Safety of Bevacizumab, Ranibizumab, and Aflibercept for Treatment of Neovascular Age-Related Macular Degeneration (AMD): A Systematic Review and Network Meta-Analysis of Direct Comparative Studies. J Clin Med. 2020;9(5):1522.

http://doi.org/10.3390/jcm9051522

Jin K, He K, Teng F, Li G, Wang H, Han N, Xu Z, Cao J, Wu J, Yu D, et al. FP3: a novel VEGF blocker with antiangiogenic effects in vitro and antitumour effects in vivo. Clin Transl Oncol. 2011;13(12):878-84.

http://doi.org/10.1007/s12094-011-0749-z

Wu Z, Zhou P, Li X, Wang H, Luo D, Qiao H, Ke X, Huang J. Structural characterization of a recombinant fusion protein by instrumental analysis and molecular modeling. PLoS One. 2013;8(3):e57642.

http://doi.org/10.1371/journal.pone.0057642

Jin K, Lan H, Cao F, Xu Z, Han N, Li G, He K, Teng L. Antitumor effect of FP3 in a patient-derived tumor tissue xenograft model of gastric carcinoma through an antiangiogenic mechanism. Oncol Lett. 2012;3(5):1052-8.

http://doi.org/10.3892/ol.2012.603

Wang F, Bai Y, Yu W, Han N, Huang L, Zhao M, Zhou A, Zhao M, Li X. Anti-angiogenic effect of KH902 on retinal neovascularization. Graefes Arch Clin Exp Ophthalmol. 2013;251(9):2131-9.

http://doi.org/10.1007/s00417-013-2392-6

Wang Q, Li T, Wu Z, Wu Q, Ke X, Luo D, Wang H. Novel VEGF decoy receptor fusion protein conbercept targeting multiple VEGF isoforms provide remarkable anti-angiogenesis effect in vivo. PLoS One. 2013;8(8):e70544.

http://doi.org/10.1371/journal.pone.0070544

Hussain RM, Shaukat BA, Ciulla LM, Berrocal AM, Sridhar J. Vascular Endothelial Growth Factor Antagonists: Promising Players in the Treatment of Neovascular Age-Related Macular Degeneration. Drug Des Devel Ther. 2021;15:2653-65.

http://doi.org/10.2147/DDDT.S295223

Ferro Desideri L, Traverso CE, Nicolò M. An update on conbercept to treat wet age-related macular degeneration. Drugs Today (Barc). 2020;56(5):311-20.

http://doi.org/10.1358/dot.2020.56.5.3137164

Li F, Zhang L, Wang Y, Xu W, Jiao W, Ma A, Zhao B. One-Year Outcome of Conbercept Therapy for Diabetic Macular Edema. Curr Eye Res. 2018;43(2):218-23.

http://doi.org/10.1080/02713683.2017.1379542

Smith LE, Wesolowski E, McLellan A, Kostyk SK, D'Amato R, Sullivan R, D'Amore PA. Oxygen-induced retinopathy in the mouse. Investigative ophthalmology & visual science. 1994;35(1):101-11.

Yang N, Zhang W, He T, Xing Y. Silencing of galectin-1 inhibits retinal neovascularization and ameliorates retinal hypoxia in a murine model of oxygen-induced ischemic retinopathy. Exp Eye Res. 2017;159:1-15.

http://doi.org/10.1016/j.exer.2017.02.015

Croci DO, Cerliani JP, Dalotto-Moreno T, Mendez-Huergo SP, Mascanfroni ID, Dergan-Dylon S, Toscano MA, Caramelo JJ, Garcia-Vallejo JJ, Ouyang J, et al. Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell. 2014;156(4):744-58.

http://doi.org/10.1016/j.cell.2014.01.043

Kanda A, Noda K, Saito W, Ishida S. Aflibercept Traps Galectin-1, an Angiogenic Factor Associated with Diabetic Retinopathy. Sci Rep. 2015;5:17946.

http://doi.org/10.1038/srep17946

Yang N, Zhang W, He T, Xing Y. Suppression of Retinal Neovascularization by Inhibition of Galectin-1 in a Murine Model of Oxygen-Induced Retinopathy. Journal of ophthalmology. 2017;2017:5053035.

http://doi.org/10.1155/2017/5053035

Yang N, Zhang W, He T, Xing Y. Exogenous erythropoietin aggravates retinal neovascularizationin a murine model of proliferative retinopathy. Turk J Med Sci. 2017;47(5):1642-50.

http://doi.org/10.3906/sag-1609-49

Saito Y, Uppal A, Byfield G, Budd S, Hartnett ME. Activated NAD(P)H oxidase from supplemental oxygen induces neovascularization independent of VEGF in retinopathy of prematurity model. Invest Ophthalmol Vis Sci. 2008;49(4):1591-8.

http://doi.org/10.1167/iovs.07-1356

Zhong X, Huang H, Shen J, Zacchigna S, Zentilin L, Giacca M, Vinores SA. Vascular endothelial growth factor-B gene transfer exacerbates retinal and choroidal neovascularization and vasopermeability without promoting inflammation. Mol Vis. 2011;17:492-507.

Chen X, Li J, Li M, Zeng M, Li T, Xiao W, Li J, Wu Q, Ke X, Luo D, et al. KH902 suppresses high glucose-induced migration and sprouting of human retinal endothelial cells by blocking VEGF and PIGF. Diabetes Obes Metab. 2013;15(3):224-33.

http://doi.org/10.1111/dom.12008

Michan S, Juan AM, Hurst CG, Cui Z, Evans LP, Hatton CJ, Pei DT, Ju M, Sinclair DA, Smith LE, et al. Sirtuin1 over-expression does not impact retinal vascular and neuronal degeneration in a mouse model of oxygen-induced retinopathy. PLoS One. 2014;9(1):e85031.

http://doi.org/10.1371/journal.pone.0085031

Sennlaub F, Courtois Y, Goureau O. Inducible nitric oxide synthase mediates retinal apoptosis in ischemic proliferative retinopathy. J Neurosci. 2002;22(10):3987-93.

http://doi.org/20026405

Connor KM, Krah NM, Dennison RJ, Aderman CM, Chen J, Guerin KI, Sapieha P, Stahl A, Willett KL, Smith LE. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc. 2009;4(11):1565-73.

http://doi.org/10.1038/nprot.2009.187

Hoang MV, Smith LE, Senger DR. Moderate GSK-3beta inhibition improves neovascular architecture, reduces vascular leakage, and reduces retinal hypoxia in a model of ischemic retinopathy. Angiogenesis. 2010;13(3):269-77.

http://doi.org/10.1007/s10456-010-9184-y

Li Z, He T, Du K, Xing YQ, Run YM, Yan Y, Shen Y. Inhibition of oxygen-induced ischemic retinal neovascularization with adenoviral 15-lipoxygenase-1 gene transfer via up-regulation of PPAR-gamma and down-regulation of VEGFR-2 expression. PLoS One. 2014;9(1):e85824.

http://doi.org/10.1371/journal.pone.0085824

Mamalis AA, Cochran DL. The role of hypoxia in the regulation of osteogenesis and angiogenesis coupling in intraoral regenerative procedures: a review of the literature. Int J Periodontics Restorative Dent. 2013;33(4):519-24.

http://doi.org/10.11607/prd.0868

Schonenberger MJ, Kovacs WJ. Hypoxia signaling pathways: modulators of oxygen-related organelles. Front Cell Dev Biol. 2015;3:42.

http://doi.org/10.3389/fcell.2015.00042

D'Andrea FP, Safwat A, Burns JS, Kassem M, Horsman MR, Overgaard J. Tumour microenvironment and radiation response in sarcomas originating from tumourigenic human mesenchymal stem cells. Int J Radiat Biol. 2012;88(6):457-65.

http://doi.org/10.3109/09553002.2012.683509

Ragnum HB, Vlatkovic L, Lie AK, Axcrona K, Julin CH, Frikstad KM, Hole KH, Seierstad T, Lyng H. The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer. Br J Cancer. 2015;112(2):382-90.

http://doi.org/10.1038/bjc.2014.604

Zou J, Yang J, Zhu X, Zhong J, Elshaer A, Matsusaka T, Pastan I, Haase VH, Yang HC, Fogo AB. Stabilization of hypoxia-inducible factor ameliorates glomerular injury sensitization after tubulointerstitial injury. Kidney Int. 2021;99(3):620-31.

http://doi.org/10.1016/j.kint.2020.09.031

Campochiaro PA, Akhlaq A. Sustained suppression of VEGF for treatment of retinal/choroidal vascular diseases. Prog Retin Eye Res. 2021;83:100921.

http://doi.org/10.1016/j.preteyeres.2020.100921

Li H-Y, Yuan Y, Fu Y-H, Wang Y, Gao X-Y. Hypoxia-inducible factor-1α: A promising therapeutic target for vasculopathy in diabetic retinopathy. Pharmacol Res. 2020;159:104924.

http://doi.org/10.1016/j.phrs.2020.104924

Zhang M, Zhang J, Yan M, Li H, Yang C, Yu D. Recombinant anti-vascular endothelial growth factor fusion protein efficiently suppresses choridal neovascularization in monkeys. Mol Vis. 2008;14:37-49.

Suto K, Yamazaki Y, Morita T, Mizuno H. Crystal structures of novel vascular endothelial growth factors (VEGF) from snake venoms: insight into selective VEGF binding to kinase insert domain-containing receptor but not to fms-like tyrosine kinase-1. J Biol Chem. 2005;280(3):2126-31.

Yamaguchi M, Nakao S, Arita R, Kaizu Y, Arima M, Zhou Y, Kita T, Yoshida S, Kimura K, Isobe T, et al. Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia. Investigative ophthalmology & visual science. 2016;57(4):2264-76.

http://doi.org/10.1167/iovs.15-17

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Published

2021-12-15

How to Cite

1.
Yang N, He X, Zhang N, Xing Y. Intraocular injection of KH902 alleviates retinal hypoxia in a mouse model of oxygen-induced retinopathy. Arch Biol Sci [Internet]. 2021Dec.15 [cited 2022Aug.18];73(4):447-55. Available from: https://www.serbiosoc.org.rs/arch/index.php/abs/article/view/6913

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