Vascular Endothelial Growth Factor–Induced Retinal Permeability Is Mediated by Protein Kinase C In Vivo and Suppressed by an Orally Effective β-Isoform–Selective Inhibitor

Aiello, Lloyd Paul; Bursell, Sven Erik; Clermont, Allen C.; Duh, Elia J.; Ishii, Hiromichi; Takagi, Chikako; Mori, Fumihiko; Ciulla, Thomas A.; Ways, Kirk; Jirousek, Michael R.; Smith, Lois E.H.; King, George L.

doi:10.2337/diab.46.9.1473

Cited by 537 publications

(198 citation statements)

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“…In the present study we demonstrate that, in the retina, VEGF protein content increases as a consequence of diabetes and this enhancement is prevented by the in vivo concomitant treatment with a selective inhibitor of PKCβ. These findings are in agreement with other studies [43,44] reporting that the inhibition of PKCβ pathway hampers VEGF and some of the VEGF-induced vascular dysfunctions. Within this context, the few clinical trials performed with the PKCβ inhibitor ruboxistaurin (LY333531) show that this inhibitor, even though moderately reduces the incidence of visual loss, seems not to affect the progression of proliferative diabetic retinopathy [45].…”

Section: Discussionsupporting

confidence: 93%

“…It has been shown that the expression of this angiogenic factor is increased by elevated glucose levels, even in early stage of diabetes [43], and prevented by general PKC inhibitors [31,44,45]. In the present study we demonstrate that, in the retina, VEGF protein content increases as a consequence of diabetes and this enhancement is prevented by the in vivo concomitant treatment with a selective inhibitor of PKCβ.…”

Section: Discussionsupporting

confidence: 69%

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The PKCβ/HuR/VEGF pathway in diabetic retinopathy

Amadio¹,

Bucolo²,

Leggio³

et al. 2010

Biochemical Pharmacology

100

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 69%

The PKCβ/HuR/VEGF pathway in diabetic retinopathy

Amadio¹,

Bucolo²,

Leggio³

et al. 2010

Biochemical Pharmacology

100

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“…19,20 CGP 41251 is also an inhibitor of phosphorylation by VEGF and PDGF receptors. As previous studies with agents that specifically block PKC␤ isoforms or specifically antagonize VEGF have resulted in only partial inhibition of retinal neovascularization, it may be that the greater efficacy of CGP 41251 is due to an additive effect of these different activities.…”

Section: Discussionmentioning

confidence: 99%

“…17 Intracellular signaling induced by VEGF is complex, but it has been suggested that protein kinase C (PKC), particularly the PKC␤II isoform, plays a prominent role. 18,19 A specific antagonist of PKC␤ isoforms partially inhibits retinal neovascularization after laser-induced branch vein occlusion. 20 Integrins ␣ v ␤ 3 and ␣ v ␤ 5 are induced on endothelial cells, including those in the retina, participating in neovascularization.…”

mentioning

confidence: 99%

Dramatic Inhibition of Retinal and Choroidal Neovascularization by Oral Administration of a Kinase Inhibitor

Seo

Kwak

Ozaki

et al. 1999

The American Journal of Pathology

159

113

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The most common cause of new blindness in young patients is retinal neovascularization , and in the elderly is choroidal neovascularization. Therefore, there has been a great deal of attention focused on the development of new treatments for these disease processes. Previous studies have demonstrated partial inhibition of retinal neovascularization in animal models using antagonists of vascular endothelial growth factor or other signaling molecules implicated in the angiogenesis cascade. These studies have indicated potential for drug treatment , but have left many questions unanswered. Is it possible to completely inhibit retinal neovascularization using drug treatment with a mode of administration that is feasible to use in patients? Do agents that inhibit retinal neovascularization have any effect on choroidal neovascularization? In this study , we demonstrate complete inhibition of retinal neovascularization in mice with oxygen-induced ischemic retinopathy by oral administration of a partially selective kinase inhibitor that blocks several members of the protein kinase C family , along with vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases. The drug also blocks normal vascularization of the retina during development but has no identifiable adverse effects on mature retinal vessels. In addition, the kinase inhibitor causes dramatic inhibition of choroidal neovascularization in a laser-induced murine model. These data provide proof of concept that pharmacological treatment is a viable approach for therapy of both retinal and choroidal neovascularization. (Am J Pathol 1999, 154:1743-1753)The retina receives its blood supply from two vascular beds: retinal vessels, which supply the inner two-thirds of the retina, and choroidal vessels, which supply the outer one-third. Damage to retinal blood vessels resulting in closure of retinal capillaries and retinal ischemia occurs in several disease processes, including diabetic retinopathy, retinopathy of prematurity, branch retinal vein occlusion, and central retinal vein occlusion; they are collectively referred to as ischemic retinopathies. Retinal ischemia results in release of one or more angiogenic factors that stimulate neovascularization. The new vessels break through the internal limiting membrane that lines the inner surface of the retina and grow along the outer surface of the vitreous. They recruit many other cells and produce sheets of vessels, cells, and extracellular matrix that exert traction on the retina, often leading to retinal detachment and severe loss of vision. Panretinal laser photocoagulation increases oxygenation in the retina and can result in involution of neovascularization. 1 However, despite the effectiveness of laser photocoagulation, 2 diabetic retinopathy remains the most common cause of severe vision loss in patients less than 60 years

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“…Pathological activation of PKC has been previously reported in the aorta, heart (10), kidney (11), and retina (12,13) in diabetic animals. The activation of PKC was also found to be closely related to the development of complications of diabetes such as atherosclerosis, retinopathy, and nephropathy (14,15).…”

mentioning

confidence: 81%

Phosphorylation of Pleckstrin Increases Proinflammatory Cytokine Secretion by Mononuclear Phagocytes in Diabetes Mellitus

Ding

Kantarcı

Badwey

et al. 2007

The Journal of Immunology

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The protein kinase C (PKC) family of intracellular enzymes plays a crucial role in signal transduction for a variety of cellular responses of mononuclear phagocytes including phagocytosis, oxidative burst, and secretion. Alterations in the activation pathways of PKC in a variety of cell types have been implicated in the pathogenesis of the complications of diabetes. In this study, we investigated the consequences of PKC activation by evaluating endogenous phosphorylation of PKC substrates with a phosphospecific PKC substrate Ab (pPKC(s)). Phosphorylation of a 40-kDa protein was significantly increased in mononuclear phagocytes from diabetics. Phosphorylation of this protein is downstream of PKC activation and its phosphorylated form was found to be associated with the membrane. Mass spectrometry analysis, immunoprecipitation, and immunoblotting experiments revealed that this 40-kDa protein is pleckstrin. We then investigated the phosphorylation and translocation of pleckstrin in response to the activation of receptor for advanced glycation end products (RAGE). The results suggest that pleckstrin is involved in RAGE signaling and advanced glycation end product (AGE)-elicited mononuclear phagocyte dysfunction. Suppression of pleckstrin expression with RNA interference silencing revealed that phosphorylation of pleckstrin is an important intermediate in the secretion and activation pathways of proinflammatory cytokines (TNF-α and IL-1β) induced by RAGE activation. In summary, this study demonstrates that phosphorylation of pleckstrin is up-regulated in diabetic mononuclear phagocytes. The phosphorylation is in part due to the activation of PKC through RAGE binding, and pleckstrin is a critical molecule for proinflammatory cytokine secretion in response to elevated AGE in diabetes.

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Vascular Endothelial Growth Factor–Induced Retinal Permeability Is Mediated by Protein Kinase C In Vivo and Suppressed by an Orally Effective β-Isoform–Selective Inhibitor

Cited by 537 publications

References 0 publications

The PKCβ/HuR/VEGF pathway in diabetic retinopathy

The PKCβ/HuR/VEGF pathway in diabetic retinopathy

Dramatic Inhibition of Retinal and Choroidal Neovascularization by Oral Administration of a Kinase Inhibitor

Phosphorylation of Pleckstrin Increases Proinflammatory Cytokine Secretion by Mononuclear Phagocytes in Diabetes Mellitus

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