Roles of LOX-1 and Stress-Activated Kinases in Retinal Dysfunction during Early Diabetes
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abstract
Retinopathy is a major complication of diabetes mellitus and a leading cause of blindness. Treatment modalities for restoring retinal function are relatively ineffective. Although proper retinal function relies on a sufficient supply of blood flo and alterations of both neural and vascular retina have been reported, the mechanism and temporal relationship between neural retina damage and vasomotor function remains unclear. Therefore, simultaneous assessment and unveiling the mechanism of vascular and neural changes in the retina during early diabetes is vital to our understanding of the retinal pathogenesis as well as to development of new therapies for early treatment. Although oxidative stress is implicated in retinal damage in diabetic retinopathy, clinical therapy with antioxidants has been mostly ineffective, suggesting other mechanisms may be involved in sustaining vasomotor and neural retina dysfunction. Also, development of an animal model of diabetes relevant to the human retinal microcirculation and its pathophysiology is lacking. To address these clinically important issues, we have developed a streptozocin-induced type 1 diabetes model in the pig, an animal model that we have shown to resemble the human in retinal vasomotor regulation and dysregulation. Our preliminary data show that within 2 wk of diabetes, endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles is impaired. Elevation of superoxide within diabetic retinal arterioles was observed but antioxidants did not improve endothelium-dependent dilation. Vasomotor impairment was improved by blockade of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), proteasomes or phosphorylation of c-Jun N- terminal kinase-1 (JNK1). LOX-1 and JNK1 are implicated in cardiovascular diseases possibly by altering endothelial NO synthase activity, but their signaling associated with retinal vascular disease remains unknown. Since scotopic b-wave amplitude is also reduced during 6-wk but not 2-wk diabetes, it appears vasomotor dysfunction precedes inner neural retina damage. Thus, the goal of this study is to delineate the link between LOX-1 and JNK1 in the retinal endothelial dysfunction and to determine whether these two molecules can serve as novel targets for improving retinal arteriolar function, along with secondary ameliorationof neural retina function, during early diabetes. We will test the hypothesis that early diabetes initiates superoxide-dependent upregulation of LOX-1 and subsequent downstream JNK1/ubiquitin-proteasome signaling for sustained degradation of SIRT1 in the retinal arteriolar endothelium, which leads to reduction of NO-mediated dilation prior to neural retina dysfunction. We will pursue two specific aims: (1) Determine the contributions of superoxide and LOX-1 to diabetes-induced endothelial dysfunction of retinal arterioles prior to neural retina damage; (2) Delineate the contribution of JNK1-dependent phosphorylation and ubiquitin-proteasome degradation of SIRT1 to diabetes-induced endothelial dysfunction of retinal arterioles. Outcomes from basic findings will be translated to therapeutic treatment of retinal vascular disease via siRNA technology in early diabetes.
