Human Leukocyte/Endothelial Cell Interactions and Mitochondrial Dysfunction in Type 2 Diabetic Patients and Their Association With Silent Myocardial Ischemia
- Antonio Hernandez-Mijares, MD, PHD1,2,3,4⇑,
- Milagros Rocha, PHD1,3,4,
- Susana Rovira-Llopis, PHD1,3,4,
- Celia Bañuls, PHD1,3,4,
- Lorena Bellod, PHD1,3,4,
- Carmen de Pablo, PHD5,
- Angeles Alvarez, PHD5,6,
- Ildefonso Roldan-Torres, MD7,
- Eva Sola-Izquierdo, MD, PHD1 and
- Victor M. Victor, PHD1,3,4,5,8⇑
- 1Service of Endocrinology, University Hospital Doctor Peset, Valencia, Spain
- 2Department of Medicine, University of Valencia,Valencia, Spain
- 3Foundation for the Promotion of Healthcare and Biomedical Research in the Valencian Community (FISABIO), Valencia, Spain
- 4INCLIVA Foundation, Valencia, Spain
- 5Department of Pharmacology and CIBER CB06/04/0071 Research Group, CIBER Hepatic and Digestive Diseases, University of Valencia, Valencia, Spain
- 6General Foundation of the University of Valencia, Valencia, Spain
- 7Cardiology Service, University Hospital Doctor Peset, Valencia, Spain
- 8Department of Physiology, University of Valencia, Valencia, Spain
- Corresponding authors: Antonio Hernandez-Mijares, , and Victor M. Victor, .
A.H.-M. and M.R. contributed equally to this study.
OBJECTIVE Diabetes is associated with oxidative stress and increased mortality, but a possible correlation between leukocyte-endothelium interactions, oxidative stress, and silent myocardial ischemia (SMI) is yet to be confirmed.
RESEARCH DESIGN AND METHODS Mitochondrial dysfunction and interactions between leukocytes and human umbilical vein endothelial cells were evaluated in 200 type 2 diabetic patients (25 with SMI) and 60 body composition– and age-matched control subjects. A possible correlation between these parameters and the onset of SMI was explored, and anthropometric and metabolic parameters were also analyzed.
RESULTS Waist, levels of triglycerides, proinflammatory cytokines (interleukin-6 and tumor necrosis factor-α), HbA1c, high-sensitivity C-reactive protein (hs-CRP), glucose, and insulin, and homeostasis model assessment of insulin resistance were higher in diabetic patients than in control subjects. However, no statistical differences in hs-CRP and insulin levels were detected when the data were adjusted for waist. None of these parameters varied between SMI and non-SMI patients. Mitochondrial function was impaired and leukocyte-endothelium interactions were more frequent among diabetic patients, which was evident in the lower mitochondrial O2 consumption, membrane potential, polymorphonuclear cell rolling velocity, and GSH/GSSG ratio, and in the higher mitochondrial reactive oxygen species production and rolling flux, adhesion, and vascular cell adhesion molecule-1 (VCAM-1) and E-selectin molecules observed in these subjects. Moreover, these differences correlated with SMI. Statistical differences were maintained after adjusting the data for BMI and waist, with the exception of VCAM-1 levels when adjusted for waist.
CONCLUSIONS Oxidative stress, mitochondrial dysfunction, and endothelium-inducing leukocyte-endothelium interactions are features of type 2 diabetes and correlate with SMI.
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc12-1224/-/DC1.
- Received June 25, 2012.
- Accepted December 1, 2012.
- © 2013 by the American Diabetes Association.
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