Inhibition of Pathological Retinal Neovascularization by a Small Peptide Derived from Human Tissue-Type Plasminogen Kringle 2.

Qian Sun,Li Su,Xun Xu,Yinchen Shen

doi:10.3389/fphar.2019.01639

Abstract

Retinal neovascularization is a hallmark pathological process of numerous ocular diseases which comprise the most common causes of blindness and affect millions of people from infants to the elderly. Compared to large proteins, small peptides have advantages for therapeutic application in ocular diseases, especially for retinal diseases. In this study, we investigated a small peptide derived from human tissue-type plasminogen kringle 2 (t-PA kringle 2), named TKII-12, and investigated the effect of TKII-12 on various aspects of vascular endothelial growth factor (VEGF)-induced angiogenesis in vitro and in vivo. Our results showed that TKII-12 effectively inhibited VEGF-induced human retinal microvascular endothelial cell proliferation, migration and tube formation on Matrigel dose-dependently as well as sequence-dependently. TKII-12 inhibited VEGF-induced formation of actin stress fibers and focal adhesions in vascular endothelial cells. Moreover, TKII-12 effectively inhibited retinal neovascularization in a mouse oxygen-induced retinopathy (OIR) model. Our study demonstrated that TKII-12 could effectively inhibit retinal angiogenesis in vitro and in vivo by eliminating the formation of focal adhesion complexes and the organization of actin stress fibers. TKII-12 can serve as a prototype for retinal angiogenesis inhibitory drug development.

Highlights

Retinal neovascularization is a hallmark pathological process of numerous ocular diseases, such as proliferative diabetic retinopathy, ischemic retinal vein occlusion, and retinopathy of prematurity
Our previous study demonstrated that one of these four peptides, TKII-10, which consisted of the Arg54-Trp63 amino acid of human type plasminogen activator (t-PA) kringle 2, inhibited vascular endothelial growth factor (VEGF) stimulated migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and effectively inhibited angiogenesis in chick chorioallantoic membrane and VEGF-induced corneal neovascularization (Su et al, 2010). We investigated another small peptide derived from human t-PA kringle 2, named TKII-12, and explored the antiangiogenic effects of TKII-12 in vitro and in vivo, in an effort to search for a more effective antiangiogenic agent for the treatment of neovascular retinopathies
In our previous study (Zhao et al, 2009), we developed a small peptide KV11(YTMNPRKLFDY)from human apolipoprotein (a) KV which can effectively inhibit retinal pathologic angiogenesis at the dose of 50 mM (1 μl) in oxygen-induced retinopathy (OIR) model

Summary

Introduction

Retinal neovascularization is a hallmark pathological process of numerous ocular diseases, such as proliferative diabetic retinopathy, ischemic retinal vein occlusion, and retinopathy of prematurity. In the past two decades, antivascular endothelial growth factor (VEGF) medications for neovascular ocular diseases have revolutionized the treatment paradigm for millions of patients and preserved their vision. The most widely used retinal angiogenesis inhibitors, such as ranibizumab, aflibercept, and bevacizumab, are large and complex proteins, that are difficult to scavenge and expensive to manufacture (Avery et al, 2017). Compared to these proteins, small peptides have advantages for therapeutic application, due to their high solubility, increased bio-availability and lack of immune response in the host cell. Designing and developing peptides for therapeutic application to inhibit angiogenesis is an important area in antiangiogenic drug development (Sulochana and Ge, 2007; Kaspar and Reichert, 2013; Agyei et al, 2017; Lau and Dunn, 2018)

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