CAMKII as a therapeutic target for growth factor-induced retinal and choroidal neovascularisation

Sadaf Ashraf, Samuel Bell, Caitriona O'Leary, Paul Canning, Ileana Micu, Jose A Fernandez, Michael O'Hare, Peter Barabas, Hannah McCauley, Derek P Brazil, Alan W Stitt, J Graham McGeown, Tim M Curtis

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

While anti-VEGF drugs are commonly used to inhibit pathological retinal and choroidal neovascularization, not all patients respond in an optimal manner. Mechanisms underpinning resistance to anti-VEGF therapy include the upregulation of other pro-angiogenic factors. Therefore, therapeutic strategies that simultaneously target multiple growth factor signalling pathways would have significant value. Here, we show that Ca2+/calmodulin-dependent kinase II (CAMKII) mediates the angiogenic actions of a range of growth factors in human retinal endothelial cells and that this kinase acts as a key nodal point for the activation of several signal transduction cascades that are known to play a critical role in growth factor-induced angiogenesis. We also demonstrate that endothelial CAMKIIγ and δ isoforms differentially regulate the angiogenic effects of different growth factors and that genetic deletion of these isoforms suppresses pathological retinal and choroidal neovascularisation in vivo. Our studies suggest that CAMKII could provide a novel and efficacious target to inhibit multiple angiogenic signalling pathways for the treatment of vasoproliferative diseases of the eye. CAMKIIγ represents a particularly promising target, as deletion of this isoform inhibited pathological neovascularisation, whilst enhancing reparative angiogenesis in the ischemic retina.

LanguageEnglish
Article numbere122442
Number of pages18
JournalJCI insight
Volume4
Issue number6
Early online date05 Feb 2019
DOIs
Publication statusPublished - 21 Mar 2019

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Retinal Neovascularization
Choroidal Neovascularization
Calcium-Calmodulin-Dependent Protein Kinases
Pathologic Neovascularization
Intercellular Signaling Peptides and Proteins
Protein Isoforms
Vascular Endothelial Growth Factor A
Eye Diseases
Angiogenesis Inducing Agents
Therapeutics
Retina
Signal Transduction
Phosphotransferases
Up-Regulation
Endothelial Cells
Pharmaceutical Preparations

Cite this

Ashraf, Sadaf ; Bell, Samuel ; O'Leary, Caitriona ; Canning, Paul ; Micu, Ileana ; Fernandez, Jose A ; O'Hare, Michael ; Barabas, Peter ; McCauley, Hannah ; Brazil, Derek P ; Stitt, Alan W ; McGeown, J Graham ; Curtis, Tim M. / CAMKII as a therapeutic target for growth factor-induced retinal and choroidal neovascularisation. In: JCI insight. 2019 ; Vol. 4, No. 6.
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CAMKII as a therapeutic target for growth factor-induced retinal and choroidal neovascularisation. / Ashraf, Sadaf; Bell, Samuel; O'Leary, Caitriona; Canning, Paul; Micu, Ileana; Fernandez, Jose A; O'Hare, Michael; Barabas, Peter; McCauley, Hannah; Brazil, Derek P; Stitt, Alan W; McGeown, J Graham; Curtis, Tim M.

In: JCI insight, Vol. 4, No. 6, e122442, 21.03.2019.

Research output: Contribution to journalArticle

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T1 - CAMKII as a therapeutic target for growth factor-induced retinal and choroidal neovascularisation

AU - Ashraf, Sadaf

AU - Bell, Samuel

AU - O'Leary, Caitriona

AU - Canning, Paul

AU - Micu, Ileana

AU - Fernandez, Jose A

AU - O'Hare, Michael

AU - Barabas, Peter

AU - McCauley, Hannah

AU - Brazil, Derek P

AU - Stitt, Alan W

AU - McGeown, J Graham

AU - Curtis, Tim M

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AB - While anti-VEGF drugs are commonly used to inhibit pathological retinal and choroidal neovascularization, not all patients respond in an optimal manner. Mechanisms underpinning resistance to anti-VEGF therapy include the upregulation of other pro-angiogenic factors. Therefore, therapeutic strategies that simultaneously target multiple growth factor signalling pathways would have significant value. Here, we show that Ca2+/calmodulin-dependent kinase II (CAMKII) mediates the angiogenic actions of a range of growth factors in human retinal endothelial cells and that this kinase acts as a key nodal point for the activation of several signal transduction cascades that are known to play a critical role in growth factor-induced angiogenesis. We also demonstrate that endothelial CAMKIIγ and δ isoforms differentially regulate the angiogenic effects of different growth factors and that genetic deletion of these isoforms suppresses pathological retinal and choroidal neovascularisation in vivo. Our studies suggest that CAMKII could provide a novel and efficacious target to inhibit multiple angiogenic signalling pathways for the treatment of vasoproliferative diseases of the eye. CAMKIIγ represents a particularly promising target, as deletion of this isoform inhibited pathological neovascularisation, whilst enhancing reparative angiogenesis in the ischemic retina.

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