Mark B Zimering1, Zui Pan. 1. Medical Service111, Department of Veterans Affairs New Jersey Health Care System, 151 Knollcroft Road, Lyons, New Jersey 07939, USA. mark.zimering@med.va.gov
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 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.
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 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.
Authors: Daniel A Winer; Shawn Winer; Lei Shen; Persis P Wadia; Jason Yantha; Geoffrey Paltser; Hubert Tsui; Ping Wu; Matthew G Davidson; Michael N Alonso; Hwei X Leong; Alec Glassford; Maria Caimol; Justin A Kenkel; Thomas F Tedder; Tracey McLaughlin; David B Miklos; H-Michael Dosch; Edgar G Engleman Journal: Nat Med Date: 2011-04-17 Impact factor: 53.440
Authors: Marinella Ruospo; Valeria M Saglimbene; Suetonia C Palmer; Salvatore De Cosmo; Antonio Pacilli; Olga Lamacchia; Mauro Cignarelli; Paola Fioretto; Mariacristina Vecchio; Jonathan C Craig; Giovanni Fm Strippoli Journal: Cochrane Database Syst Rev Date: 2017-06-08