Beta-adrenergic Receptor Agonist Decreases VEGF Levels Through Altered ENOS and PKC Signaling in Diabetic Retina

Overview

Journal Growth Factors

Publisher Informa Healthcare

Specialty Biology

Date 2015 Jun 27

PMID 26115368

Citations 13

Authors

Youde Jiang

Qiuhua Zhang

Jena J Steinle

Affiliations

Soon will be listed here.

Abstract

Vascular endothelial cell growth factor (VEGF) is increased in diabetic macular edema. Compound 49b, a novel β-adrenergic receptor agonist, is protective in a type 1 diabetic rat model. We questioned whether Compound 49b could decrease VEGF levels, suggesting that Compound 49b may be effective against edema. Two-month diabetic rats received topical Compound 49b for 7 days only and/or insulin-like growth factor binding protein 3 (IGFBP-3) siRNA. We also measured endothelial nitric oxide synthase (eNOS) and protein kinase C (PKC)ζ and PKCδ phosphorylation. Retinal endothelial cells (RECs) cultured in high glucose were treated with Compound 49b and IGFBP-3 siRNA for evaluation of the same signaling pathways. Compound 49b significantly decreased VEGF through increased IGFBP-3 in the diabetic retina. Compound 49b also reduced eNOS, PKCζ and PKCδ phosphorylation in the diabetic retina and REC. Compound 49b regulated a number of proteins involved in REC barrier properties.

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References

Koizumi K, Poulaki V, Doehmen S, Welsandt G, Radetzky S, Lappas A . Contribution of TNF-alpha to leukocyte adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis in vivo. Invest Ophthalmol Vis Sci. 2003; 44(5):2184-91. DOI: 10.1167/iovs.02-0589. View

Harhaj N, Felinski E, Wolpert E, Sundstrom J, Gardner T, Antonetti D . VEGF activation of protein kinase C stimulates occludin phosphorylation and contributes to endothelial permeability. Invest Ophthalmol Vis Sci. 2006; 47(11):5106-15. DOI: 10.1167/iovs.06-0322. View

Kielczewski J, Jarajapu Y, McFarland E, Cai J, Afzal A, Li Calzi S . Insulin-like growth factor binding protein-3 mediates vascular repair by enhancing nitric oxide generation. Circ Res. 2009; 105(9):897-905. PMC: 3635679. DOI: 10.1161/CIRCRESAHA.109.199059. View

Kim J, Kim J, Jun H, Yu Y, Kim K . Inhibition of protein kinase C delta attenuates blood-retinal barrier breakdown in diabetic retinopathy. Am J Pathol. 2010; 176(3):1517-24. PMC: 2832170. DOI: 10.2353/ajpath.2010.090398. View

Wang L, Wu B, Sun Y, Xu T, Zhang X, Zhou M . Translocation of protein kinase C isoforms is involved in propofol-induced endothelial nitric oxide synthase activation. Br J Anaesth. 2010; 104(5):606-12. DOI: 10.1093/bja/aeq064. View

Geraldes P, King G . Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res. 2010; 106(8):1319-31. PMC: 2877591. DOI: 10.1161/CIRCRESAHA.110.217117. View

Aveleira C, Lin C, Abcouwer S, Ambrosio A, Antonetti D . TNF-α signals through PKCζ/NF-κB to alter the tight junction complex and increase retinal endothelial cell permeability. Diabetes. 2010; 59(11):2872-82. PMC: 2963546. DOI: 10.2337/db09-1606. View

Park S, Kang J, Jeong K, Lee J, Han J, Choi W . Norepinephrine induces VEGF expression and angiogenesis by a hypoxia-inducible factor-1α protein-dependent mechanism. Int J Cancer. 2010; 128(10):2306-16. DOI: 10.1002/ijc.25589. View

Frey T, Antonetti D . Alterations to the blood-retinal barrier in diabetes: cytokines and reactive oxygen species. Antioxid Redox Signal. 2011; 15(5):1271-84. DOI: 10.1089/ars.2011.3906. View

10.

Omri S, Behar-Cohen F, de Kozak Y, Sennlaub F, Verissimo L, Jonet L . Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKCζ in the Goto Kakizaki rat model. Am J Pathol. 2011; 179(2):942-53. PMC: 3157258. DOI: 10.1016/j.ajpath.2011.04.018. View

11.

Googe J, Brucker A, Bressler N, Qin H, Aiello L, Antoszyk A . Randomized trial evaluating short-term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema after focal/grid laser for diabetic macular edema in eyes also receiving panretinal photocoagulation. Retina. 2011; 31(6):1009-27. PMC: 3489032. DOI: 10.1097/IAE.0b013e318217d739. View

12.

Kielczewski J, Li Calzi S, Shaw L, Cai J, Qi X, Ruan Q . Free insulin-like growth factor binding protein-3 (IGFBP-3) reduces retinal vascular permeability in association with a reduction of acid sphingomyelinase (ASMase). Invest Ophthalmol Vis Sci. 2011; 52(11):8278-86. PMC: 3208060. DOI: 10.1167/iovs.11-8167. View

13.

Barbieri A, Palma G, Rosati A, Giudice A, Falco A, Petrillo A . Role of endothelial nitric oxide synthase (eNOS) in chronic stress-promoted tumour growth. J Cell Mol Med. 2011; 16(4):920-6. PMC: 3822860. DOI: 10.1111/j.1582-4934.2011.01375.x. View

14.

Dal Monte M, Martini D, Latina V, Pavan B, Filippi L, Bagnoli P . Beta-adrenoreceptor agonism influences retinal responses to hypoxia in a model of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2012; 53(4):2181-92. DOI: 10.1167/iovs.11-9408. View

15.

Zhang Q, Guy K, Pagadala J, Jiang Y, Walker R, Liu L . Compound 49b prevents diabetes-induced apoptosis through increased IGFBP-3 levels. Invest Ophthalmol Vis Sci. 2012; 53(6):3004-13. PMC: 3378083. DOI: 10.1167/iovs.11-8779. View

16.

Munoz Y, Gomez G, Moreno M, Solis C, Valladares L, Velarde V . Dehydroepiandrosterone prevents the aggregation of platelets obtained from postmenopausal women with type 2 diabetes mellitus through the activation of the PKC/eNOS/NO pathway. Horm Metab Res. 2012; 44(8):625-31. DOI: 10.1055/s-0032-1309056. View

17.

Jarajapu Y, Cai J, Yan Y, Li Calzi S, Kielczewski J, Hu P . Protection of blood retinal barrier and systemic vasculature by insulin-like growth factor binding protein-3. PLoS One. 2012; 7(7):e39398. PMC: 3391198. DOI: 10.1371/journal.pone.0039398. View

18.

Titchenell P, Lin C, Keil J, Sundstrom J, Smith C, Antonetti D . Novel atypical PKC inhibitors prevent vascular endothelial growth factor-induced blood-retinal barrier dysfunction. Biochem J. 2012; 446(3):455-67. PMC: 3767384. DOI: 10.1042/BJ20111961. View

19.

Dal Monte M, Filippi L, Bagnoli P . Beta3-adrenergic receptors modulate vascular endothelial growth factor release in response to hypoxia through the nitric oxide pathway in mouse retinal explants. Naunyn Schmiedebergs Arch Pharmacol. 2013; 386(4):269-78. DOI: 10.1007/s00210-012-0828-x. View

20.

Jiang Y, Zhang Q, Liu L, Tang J, Kern T, Steinle J . β2-adrenergic receptor knockout mice exhibit A diabetic retinopathy phenotype. PLoS One. 2013; 8(7):e70555. PMC: 3722144. DOI: 10.1371/journal.pone.0070555. View