OBJECTIVEDiabetes 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 METHODSMitochondrial 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.RESULTSWaist, 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.CONCLUSIONSOxidative stress, mitochondrial dysfunction, and endothelium-inducing leukocyte-endothelium interactions are features of type 2 diabetes and correlate with SMI.
Overproduction of reactive oxygen species (ROS) under pathophysiologic conditions is part of the disease process. These ROS are released from different sources, and in particular from mitochondria. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are unclear, oxidative stress seems to play an important role. ROS are essential to cell function, but adequate levels of antioxidant defenses are required in order to avoid the harmful effects that excessive ROS production can produce. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions. The antioxidants available until now have not proved to be particularly effective against many of these disorders. It is possible that these antioxidants do not reach the sites of free radical generation, especially when mitochondria are the primary source of ROS. Recent developments in mitochondria-targeted antioxidants have moved closer to providing protection against mitochondrial oxidative damage. The SS (Szeto-Schiller) peptide antioxidants represent a novel approach that employs the targeted delivery of antioxidants to the inner mitochondrial membrane. These SS peptides scavenge hydrogen peroxide and peroxynitrite and inhibit lipid peroxidation. By reducing mitochondrial ROS, they inhibit mitochondrial permeability transition and cytochrome c release, thus preventing oxidant-induced cell death. Preclinical studies support the use of these peptides for ischemia-reperfusion injury and neurodegenerative disorders. Although peptides have often been considered to be poor drug candidates, the few that have been studied are promising agents for the treatment of diseases.
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