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

Medical Service (M.B.Z.), Department of Veterans Affairs New Jersey Health Care System, Lyons, New Jersey 07939; and Departments of Medicine (M.B.Z.) and Physiology and Biophysics (Z.P.), Confocal Microscopy and Cell Imaging Core (Z.P.), University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Address all correspondence and requests for reprints to: Mark B. Zimering, M.D., Ph.D., Medical Service111, 151 Knollcroft Road, Lyons, New Jersey 07939. E-mail: mark.zimering{at}med.va.gov; or Zui Pan, Ph.D., Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 683 Hoes Lane, Piscataway, New Jersey 08854. E-mail: panzu{at}umdnj.edu.

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.