Abstract
Hyperglycemia results in inhibition of cleavage of integrin-associated protein (IAP) thereby allowing it to bind to SHPS-1 which results in pathophysiologic changes in endothelial function. This study determined if an anti-rat IAP antibody directed against the SHPS-1 binding site which disrupts IAP/SHPS-1 association could inhibit these pathophysiologic changes. The anti-IAP antibody inhibited IGF-I-stimulated SHPS-1, p52Shc, MAP kinase phosphorylation, and proliferation in endothelial cells. To determine if it could reverse established pathophysiologic changes in vivo, this antibody or normal rat IgG F(ab)2 was injected intraperitoneally for 6 weeks into rats that had diabetes for 4 weeks. Optical coherence tomography (OCT) showed that retinal thickness increased at 4 weeks and this increase was maintained in rats treated with the control antibody for an additional 6 weeks. The increase was reversed by anti-IAP antibody treatment (84.6 ± 2.0 compared to 92.3 ± 2.5 μm, p < 0.01). This value was similar to nondiabetic animals (82.2 ± 1.6 μm, p, NS). The anti-IAP antibody also decreased retinal vascular permeability (0.62 ± 0.12 vs. 0.96 ± 0.25%/g/h, p < 0.001). To determine if it was effective after local injection, this antibody or control was administered via intravitreal injection. After 3 weeks, retinal thickness increased to 6.4 ± 2.8% in diabetic rats, and IAP antibody treatment prevented this increase (0.8 ± 2.5%, p < 0.01). It also prevented the increase of retinal vascular permeability (0.92 ± 0.62 vs. 1.63 ± 0.99%/g/h, p < 0.001). Biochemical analyses of retinal extracts showed that the anti-IAP antibody inhibited IAP/SHPS-1 association and SHPS-1 phosphorylation. This resulted in inhibition of AKT activation and VEGF synthesis in the retina: changes associated with increased vascular permeability. We conclude the anti-rat IAP antibody disrupts IAP/SHPS-1 association and attenuates aberrant IGF-I signaling thereby preventing or reversing the progression of retinal pathophysiological changes.
Highlights
Diabetic retinopathy (DR) remains a major cause of severe vision impairment
To determine if the antibody directed against rat integrin-associated protein (IAP) would inhibit pathophysiologic changes that are stimulated by Ratios of scan values (SHPS-1-associated IAP/SHPS-1)
The findings in this study show that disruption of IAP/SHPS-1 association results in prevention and reversal of the early changes that occur in diabetic retinopathy
Summary
Diabetic retinopathy (DR) remains a major cause of severe vision impairment. the incidence is declining, the prevalence is increasing because of an aging population and the increase in the number of patients with diabetes [1]. IGF-I induces VEGF in multiple in vitro and in vivo models, and studies have shown that the IGF-I-induced increase in VEGF activates the VEGFR2 receptor [9, 11,12,13] Based on those studies, our laboratory has extensively analyzed IGF-I signaling in both vascular endothelial and smooth muscle cells maintained under hyperglycemic conditions. Since the SHPS-1 binding site on IAP is contained within the cleaved fragment, inhibition of cleavage results in a major increase in IAP/SHPS-1 association thereby facilitating IGF-I stimulation of pathophysiologic changes Based on those studies, we utilized a monoclonal antibody (B6H12) to disrupt IAP/SHPS-1 and showed that it attenuated IGF-I signaling and prevented an increase in retinal vascular permeability in diabetic rats [18]. We wished to determine whether the anti-IAP antibody was active following intraocular injections and whether it could attenuate the pathophysiologic changes that occur in IGF-I signal transduction in vivo
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