Abstract
Choroidal neovascularization (CNV) is aberrant angiogenesis associated with exudative age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Inflammation has been suggested as a risk factor for AMD. The IKK2/NF-κB pathway plays a key role in the inflammatory response through regulation of the transcription of cytokines, chemokines, growth factors and angiogenic factors. We investigated the functional role of IKK2 in development of the laser-induced CNV using either Ikk2 conditional knockout mice or an IKK2 inhibitor. The retinal neuronal tissue and RPE deletion of IKK2 was generated by breeding Ikk2−/flox mice with Nestin-Cre mice. Deletion of Ikk2 in the retina caused no obvious defect in retinal development or function, but resulted in a significant reduction in laser-induced CNV. In addition, intravitreal or retrobulbar injection of an IKK2 specific chemical inhibitor, TPCA-1, also showed similar inhibition of CNV. Furthermore, in vitro inhibition of IKK2 in ARPE-19 cells significantly reduced heat shock-induced expression of NFKBIA, IL1B, CCL2, VEGFA, PDGFA, HIF1A, and MMP-2, suggesting that IKK2 may regulate multiple molecular pathways involved in laser-induced CNV. The in vivo laser-induced expression of VEGFA, and HIF1A in RPE and choroidal tissue was also blocked by TPCA-1 treatment. Thus, IKK2/NF-κB signaling appears responsible for production of pro-inflammatory and pro-angiogenic factors in laser-induced CNV, suggesting that this intracellular pathway may serve as an important therapeutic target for aberrant angiogenesis in exudative AMD.
Highlights
Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in humans over 55, and affects 10 to 15 million people in the USA [1]
To assess the functional role of IKK2 in aberrant angiogenesis, we investigated the effect of Ikk2 gene deletion or chemical inhibition of IKK2 activity on development of laser-induced choroidal neovascularization (CNV), a murine model of wound healing accompanied by oxidative stress and inflammation [14,15]
We propose that the IKK2/NF-kB pathway may serve as a novel therapeutic target in the prevention or treatment of wet AMD
Summary
Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in humans over 55, and affects 10 to 15 million people in the USA [1]. FDA-approved drugs for the treatment of wet AMD include Lucentis (Ranibizumab), Eylea (Aflibercept), and Macugen (Pegaptanib), all of which target VEGF to slow the growth of abnormal blood vessels and reverse the increased vascular permeability associated with new vessel formation [3,4,5]. These drugs, as well as Avastin (Bevacizumab), have been shown to be effective in the treatment of many patients with wet AMD but they require frequent intravitreal injections and resistance to anti-VEGF monotherapy in wet AMD is apparent. Development of new therapeutic approaches or combination therapies is needed
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