Increased tumor necrosis factor-α, cleaved caspase 3 levels and insulin receptor substrate-1 phosphorylation in the ß1-adrenergic receptor knockout mouse.

ABSTRACT

PURPOSE: To investigate the role of ß1-adrenergic receptors on insulin like growth factor (IGF)-1 receptor signaling and apoptosis in the retina using ß1-adrenergic receptor knockout (KO) mice. METHODS: Western blotting and enzyme-linked immunosorbent assay analyses were done on whole retinal lysates from ß1-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 ß1-adrenergic receptor KO mice versus littermates. RESULTS: Lack of ß1-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 ß-adrenergic receptor signaling is beneficial for retinal homeostasis. Loss of ß1-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 ß-adrenergic receptor agents may provide additional avenues for therapeutics.