Ischemic retinopathies, such as
diabetic retinopathy (DR),
retinopathy of prematurity and
retinal vein occlusion are a major cause of
blindness in developed nations worldwide. Each of these conditions is associated with early neurovascular dysfunction. However, conventional
therapies target clinically significant macula
edema or neovascularization, which occur much later.
Intra-ocular injections of anti-
VEGF show promise in reducing
retinal edema, but the effects are usually transient and the need for repeated
injections increases the risk of intraocular
infection.
Laser photocoagulation can control
pathological neovascularization, but may impair vision and in some patients the retinopathy continues to progress. Moreover, neither treatment targets early stage disease or promotes repair. This review examines the potential role of the ureahydrolase
enzyme arginase as a therapeutic target for the treatment of ischemic retinopathy.
Arginase metabolizes
l-arginine to form
proline,
polyamines and
glutamate. Excessive
arginase activity reduces the
l-arginine supply for
nitric oxide synthase (NOS), causing it to become uncoupled and produce
superoxide and less NO.
Superoxide and NO react and form the toxic
oxidant peroxynitrite. The catabolic products of
polyamine oxidation and
glutamate can induce more oxidative stress and DNA damage, both of which can cause cellular injury. Studies indicate that neurovascular injury during retinopathy is associated with increased
arginase expression/activity, decreased NO,
polyamine oxidation, formation of
superoxide and
peroxynitrite and dysfunction and injury of both vascular and neural cells. Furthermore, data indicate that the cytosolic
isoform arginase I (AI) is involved in
hyperglycemia-induced dysfunction and injury of vascular endothelial cells whereas the mitochondrial
isoform arginase II (AII) is involved in neurovascular dysfunction and death following
hyperoxia exposure. Thus, we postulate that activation of the
arginase pathway causes neurovascular injury by uncoupling NOS and inducing
polyamine oxidation and
glutamate formation, thereby reducing NO and increasing oxidative stress, all of which contribute to the retinopathic process.