Beta-adrenergic receptor agonist decreases VEGF levels through altered eNOS and PKC signaling in diabetic retina

Growth Factors. 2015;33(3):192-9. doi: 10.3109/08977194.2015.1054990. Epub 2015 Jun 26.

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.

Keywords: Beta-adrenergic receptor; VEGF; diabetic retinopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology*
  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / pathology*
  • Diabetic Retinopathy / pathology*
  • Endothelial Cells / cytology
  • Insulin-Like Growth Factor Binding Protein 3 / genetics*
  • Isoenzymes / metabolism
  • Macular Edema / pathology
  • Male
  • Nitric Oxide Synthase Type III / metabolism*
  • Norepinephrine / analogs & derivatives*
  • Norepinephrine / pharmacology
  • Phenethylamines / pharmacology*
  • Protein Kinase C / metabolism*
  • Protein Kinase C-delta / metabolism
  • Protein Kinase C-theta
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Inbred Lew
  • Retina / cytology
  • Retina / pathology
  • Streptozocin
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Adrenergic beta-Agonists
  • Insulin-Like Growth Factor Binding Protein 3
  • Isoenzymes
  • Phenethylamines
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Streptozocin
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • protein kinase C zeta
  • Prkcq protein, rat
  • Protein Kinase C
  • Protein Kinase C-delta
  • Protein Kinase C-theta
  • Norepinephrine