Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression

Abstract

Many ocular pathologies, including retinopathy of prematurity (ROP), diabetic retinopathy, and age-related macular degeneration, result in vision loss because of aberrant neoangiogenesis. A common feature of these conditions is the presence of hypoxic areas and overexpression of the proangiogenic vascular endothelial growth factor (VEGF). The prevailing current treatment, laser ablation of the retina, is destructive and only partially effective. Preventive and less destructive therapies are much more desirable. Here, we show that mice lacking c-Jun N-terminal kinase 1 (JNK1) exhibit reduced pathological angiogenesis and lower levels of retinal VEGF production in a murine model of ROP. We found that hypoxia induces JNK activation and regulates VEGF expression by enhancing the binding of phospho-c-Jun to the VEGF promoter. Intravitreal injection of a specific JNK inhibitor decreases retinal VEGF expression and reduces pathological retinal neovascularization without obvious side effects. These results strongly suggest that JNK1 plays a key role in retinal neoangiogenesis and that it represents a new pharmacological target for treatment of diseases where excessive neoangiogenesis is the underlying pathology.neoangiogenesis ͉ retinopathy of prematurity

JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration

“…The decrease of VEGF in JNK1-deficient mice was expected, as JNK1 regulates VEGF expression under different stimuli such as hypoxia and inflammation (13). However, our data further suggest that JNK1 may also be involved in the initial stages of AMD.…”

“…Interestingly, it was shown that reactive oxygen species (ROS) cause JNK activation and cell death (12). We also recently showed that JNK1 is a critical factor in hypoxia-induced retinal VEGF production and that it promotes hypoxia-induced pathological angiogenesis (13). Thus, JNK1 might play a key Author contributions: M.K.…”

Activation of Cytosolic Phospholipase A2 Downstream of the Src-Phospholipase D1 (PLD1)-Protein Kinase C γ (PKCγ) Signaling Axis Is Required for Hypoxia-induced Pathological Retinal Angiogenesis

“…In view of these observations, it is conceivable that VEGF or hypoxia-induced cPLA 2 phosphorylation may not require MAPK activation. Nonetheless, studies from our laboratories as well as others have shown a role for MAPKs such as JNK1 in the regulation of retinal angiogenesis (50,51). Based on these observations, it is probable that although both cPLA 2 and MAPKs are required for VEGF or hypoxia-induced retinal angiogenesis, they appear to be acting independently of each other in response to these agonists/conditions.…”

JNK Inhibition Reduced Retinal Ganglion Cell Death after Ischemia/Reperfusion In Vivo and after Hypoxia In Vitro

“…The observation that JNK was activated in ischemic neurons highlighted its potential involvement in the apoptotic process following cerebral ischemia (Borsello et al 2003).MAPKs activation has also been investigated in retinas after ischemia. Zhang et al first made the observation that both JNK and p38 activation could be attenuated by ischemic preconditioning, suggesting that these two MAPKs were implicated in the deleterious effects induced by ischemia in the retina (Zhang et al 2002).The use of D-JNKi provided a significant protection against neuronal loss after optic nerve crush in mice and in a model of retinopathy of prematurity (Tezel et al 2004;Guma et al 2009). …”