Autoantibodies in type 2 diabetes induce stress fiber formation and apoptosis in endothelial cells.
BACKGROUND
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.


METHODS
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.


METHODS
The study was conducted in outpatient clinics.


METHODS
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.


METHODS
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 microm 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.
Zimering
Mark B
MB
Medical Service111, Department of Veterans Affairs New Jersey Health Care System, 151 Knollcroft Road, Lyons, New Jersey 07939, USA. mark.zimering@med.va.gov
Pan
Zui
Z
D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001323:Autoantibodies / Q000032:analysis / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D016022:Case-Control Studies; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000276:immunology*; D003925:Diabetic Angiopathies / Q000209:etiology / Q000276:immunology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D022502:Stress Fibers / Q000187:drug effects* / Q000378:metabolism; D017186:Titrimetry; D054460:rho-Associated Kinases / Q000502:physiology
D001323:Autoantibodies; D054460:rho-Associated Kinases