title: Increased tumor necrosis factor-α, cleaved caspase 3 levels and insulin receptor substrate-1 phosphorylation in the β₁-adrenergic receptor knockout mouse.
abstract: OBJECTIVE
  To investigate the role of β1-adrenergic receptors on insulin like growth factor (IGF)-1 receptor signaling and apoptosis in the retina using β1-adrenergic receptor knockout (KO) mice.
  
  
  METHODS
  Western blotting and enzyme-linked immunosorbent assay analyses were done on whole retinal lysates from β1-adrenergic receptor KO mice and wild-type littermates. In addition, vascular analyses of degenerate capillaries and pericyte ghosts were done on the retina of the β1-adrenergic receptor KO mice versus littermates.
  
  
  RESULTS
  Lack of β1-adrenergic receptors produced a significant increase in both degenerate capillaries and pericyte ghosts. This was accompanied by an increase in cleaved caspase 3 and tumor necrosis factor α levels. IGF-1 receptor phosphorylation was not changed; however, protein kinase B (Akt) phosphorylation was significantly decreased. The decrease in Akt phosphorylation is likely caused by increased insulin receptor substrate-1 serine 307 (IRS-1(Ser307)) phosphorylation, which is inhibitory to IGF-1 receptor signaling.
  
  
  CONCLUSIONS
  These studies further support the idea that maintenance of β-adrenergic receptor signaling is beneficial for retinal homeostasis. Loss of β1-adrenergic receptor signaling alters tumor necrosis factor α and apoptosis levels in the retina, as well as Akt and IGF-1 receptor phosphorylation. Since many of these same changes are observed in the diabetic retina, these data support that novel β-adrenergic receptor agents may provide additional avenues for therapeutics.
authors.affiliation: Department of Ophthalmology, Hamilton Eye Institute, The University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Surekha Rani
authors.initials: SR
authors.lastname: Panjala
authors.forename: Youde
authors.initials: Y
authors.lastname: Jiang
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.forename: Steven A
authors.initials: SA
authors.lastname: Thomas
authors.forename: Jena J
authors.initials: JJ
authors.lastname: Steinle
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002196:Capillaries / Q000473:pathology / Q000502:physiology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002457:Cell Extracts / Q000737:chemistry / Q000235:genetics; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003930:Diabetic Retinopathy / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020286:Pericytes / Q000473:pathology / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000172:deficiency* / Q000235:genetics; D012039:Regional Blood Flow / Q000502:physiology; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D002457:Cell Extracts; D055504:Insulin Receptor Substrate Proteins; D018342:Receptors, Adrenergic, beta-1; D014409:Tumor Necrosis Factor-alpha; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3