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 language | English |
|---|---|
| Article number | e122442 |
| Journal | JCI Insight |
| Volume | 4 |
| Issue number | 6 |
| Early online date | 5 Feb 2019 |
| DOIs | |
| Publication status | Published - 21 Mar 2019 |
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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
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 journal › Article
}
TY - JOUR
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
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.
KW - PROTEIN-KINASE-II
KW - PROLIFERATIVE DIABETIC-RETINOPATHY
KW - OXYGEN-INDUCED RETINOPATHY
KW - DELTA ISOFORM
KW - ANGIOGENESIS
KW - VEGF
KW - ACTIVATION
KW - MOUSE
KW - INHIBITION
KW - INSULIN
UR - http://www.mendeley.com/research/camkii-therapeutic-target-growth-factorinduced-retinal-choroidal-neovascularisation
UR - http://www.scopus.com/inward/record.url?scp=85070659509&partnerID=8YFLogxK
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 -