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Involvement of Protein Kinase CK2 in Angiogenesis and Retinal Neovascularization

¹From the Ophthalmology Research Laboratories, Burns and Allen Research Institute, Cedars-Sinai Medical Center, and David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; the ²Department of Pharmacology, University of Florida, Gainesville, Florida; the ³Dipartimento di Chimica Biologica, Universita di Padova, Padova, Italy; and the ⁴Department of Ophthalmology, University of California Irvine College of Medicine, Orange, California.

PURPOSE. The purpose of the study was to characterize signaling intermediates involved in angiogenic responses of retinal endothelial cells (RECs) to the extracellular matrix and growth factors, by using specific inhibitors.

METHODS. Tubelike structure formation and the development of secondary sprouts on a basement membrane (BM) matrix, cell proliferation, and cell migration were studied in cultures of bovine and human RECs. Specific inhibitors were tested for inhibition of retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR).

RESULTS. In initial experiments, the broad-spectrum protein kinase inhibitors, H7 and H89, stabilized REC tubes on BM matrix and inhibited secondary sprouting, cell migration, and cell proliferation. Among more specific kinase inhibitors tested, only inhibitors of protein kinase CK2 (formerly, casein kinase II), such as emodin and DRB, were able to duplicate the effects of H7 and H89. Actinomycin D caused only minor changes in angiogenic assays, suggesting that CK2’s effects on REC did not involve its known impact on transcription. The extent of retinal neovascularization in a mouse OIR model was reduced >70% (versus untreated or vehicle-treated groups) after treatment with emodin (6 days at 60 mg/kg per day) and by approximately 60% after treatment at the same dose with TBB, the most specific CK2 inhibitor known. In the treated retinas, the main vascular tree had minimal changes, but the neovascular tufts were greatly reduced in number or absent.

CONCLUSIONS. This is the first demonstration of the involvement of ubiquitous protein kinase CK2 in angiogenesis. Naturally derived CK2 inhibitors may be useful for treatment of proliferative retinopathies.

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