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

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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.

Original languageEnglish
Article numbere122442
JournalJCI Insight
Volume4
Issue number6
Early online date5 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

Keywords

  • PROTEIN-KINASE-II
  • PROLIFERATIVE DIABETIC-RETINOPATHY
  • OXYGEN-INDUCED RETINOPATHY
  • DELTA ISOFORM
  • ANGIOGENESIS
  • VEGF
  • ACTIVATION
  • MOUSE
  • INHIBITION
  • INSULIN

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ashraf, S., Bell, S., O'Leary, C., Canning, P., Micu, I., Fernandez, J. A., ... Curtis, T. M. (2019). CAMKII as a therapeutic target for growth factor-induced retinal and choroidal neovascularisation. JCI Insight, 4(6), [e122442]. https://doi.org/10.1172/jci.insight.122442

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

Ashraf, S, Bell, S, O'Leary, C, Canning, P, Micu, I, Fernandez, JA, O'Hare, M, Barabas, P, McCauley, H, Brazil, DP, Stitt, AW, McGeown, JG & Curtis, TM 2019, 'CAMKII as a therapeutic target for growth factor-induced retinal and choroidal neovascularisation', JCI Insight, vol. 4, no. 6, e122442. https://doi.org/10.1172/jci.insight.122442
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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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.",
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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

N1 - This study was supported by grants from the British Heart Foundation (PG/11/99/29207 and PG/11/94/29169), Fight for Sight, UK (1387/88), Health & Social Care R&D Division, Northern Ireland (STL/4748/13) and the Medical Research Council (MC_PC_15026). We would like to thank Gordon Revolta for excellent assistance with colony management and genotyping.

PY - 2019/3/21

Y1 - 2019/3/21

N2 - 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.

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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KW - PROLIFERATIVE DIABETIC-RETINOPATHY

KW - OXYGEN-INDUCED RETINOPATHY

KW - DELTA ISOFORM

KW - ANGIOGENESIS

KW - VEGF

KW - ACTIVATION

KW - MOUSE

KW - INHIBITION

KW - INSULIN

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U2 - 10.1172/jci.insight.122442

DO - 10.1172/jci.insight.122442

M3 - Article

VL - 4

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 6

M1 - e122442

ER -