Recent advances in basic research have succeeded in demonstrating that the vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of diabetic retinopathy. The clinical application of VEGF inhibitors has been found to dramatically improve visual outcome of diabetic retinopathy, and in what is called the "anti-VEGF era", we are witnessing continuous evolution in treatment strategies for diabetic retinopathy. The situation has greatly changed from when we only had a couple of clinical options, namely, photocoagulation and vitreous surgery, for advanced diabetic retinopathy. However, accumulating evidence recently obtained through basic and clinical studies on the innovation in research instruments and information system have highlighted multiple issues, such as complexity of the pathology of retinopathy, limitations of VEGF inhibition therapy, and its potential adverse effects. Therefore, new drug discover trials focusing on disease causative molecules other than VEGF are being conducted worldwide, and we are now very close to the "post anti-VEGF era" in which there will be numerous therapeutic options with multiple molecular targeted drugs for diabetic retinopathy.
It is well-known that the onset and development of diabetic retinopathy involve chronic inflammation and oxidative stress. In the current study, we sought to mainly elucidate the role of vascular adhesion protein-1 (VAP-1)/semicarbazide sensitive amine oxidase (SSAO) in diabetic retinopathy while also exploring novel target molecules such as glycans. VAP-1/SSAO is a leukocyte adhesion molecule expressed on the plasma membrane of vascular endothelial cells and VAP-1/SSAO also possesses an enzymatic activity as amine oxidase. Thus, VAP-1/SSAO is a'moonlighting protein'that is a single molecule with multiple functions. It is considered to be a potentially important drug target because of its stimulus effects on both chronic inflammation and oxidative stress pathways in the pathological condition of diabetic retinopathy. We observed that VAP-1/SSAO is not only expressed in the membrane-associated form in fibrovascular tissues but if also accumulates in the soluble form in the vitreous of patients with proliferative diabetic retinopathy. We revealed the accumulation mechanism of VAP-1/SSAO, which contributes to the increase in oxidative stress by the generation of hydrogen peroxide and unsaturated aldehyde acrolein, in the eyes of patients with diabetic retinopathy.
In this article, I will discuss recent results and the potential clinical application of VAP-1/SSAO inhibitor to diabetic retinopathy.
Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc) 122: 223-248, 2018.