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

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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.

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