Autoantibodies in Type 2 Diabetes Induce Stress Fiber Formation and Apoptosis in Endothelial Cells

Abstract

Abstract Context: Macular edema contributes to visual impairment, and albuminuria is associated with increased cardiovascular mortality in adults with type 2 diabetes mellitus. These microvascular complications result from increased capillary leakage of plasma proteins whose causation is not completely understood. Objective: The objective of the present study was to test whether plasma from type 2 diabetes with maculopathy/albuminuria or control subjects contains autoantibodies that can induce apoptosis or activate Rho kinase (ROCK) in endothelial cells. Design: A cohort of Veterans Affairs Diabetes Trial adults (>40 yr of age) was randomized to standard vs. intensive glycemic treatment lasting 5–7.5 yr. Setting: The study was conducted in outpatient clinics. Patients: Case and age-matched control subjects who differed for the baseline presence of significant diabetic maculopathy and/or progression to macro-albuminuria were included in the study. Intervention: Pharmacological and lifestyle interventions in the Veterans Affairs Diabetes Trial generally resulted in substantially improved glycemic, blood pressure, and lipid levels. Results: Autoantibodies from patients with macular edema or progression to albuminuria potently induced caspase-dependent apoptosis in endothelial cells (up to 60%), whereas IgG from age-matched normal plasma caused much less apoptosis (<10%; P < 0.0001). The active inhibitory autoantibodies triggered stress fiber formation in endothelial cells likely through the activation of Rho guanosine 5′-triphosphatase, which could be nearly completed inhibited by 10 μm Y27632, a specific ROCK inhibitor. Conclusions: These results suggest that autoantibodies from a subset of advanced type 2 diabetes may contribute to diabetic vascular complications by activating ROCK, inducing stress fiber formation and apoptosis in endothelial cells.