Prediabetes Increases Platelet Activation Via Sod2 In Young And Middle-aged Veterans

Aging is a risk factor for thrombotic cardiovascular diseases and presence of a risk factor may aggravate the outcome. Due to the increase in overweight/obese people in the aging population, the incidence of prediabetes is increasing. Recent studies suggest that prediabetes is not only a prelude to diabetes, but also it is an independent risk factor for thrombotic events. However, the prothrombotic mechanisms are not known. We hypothesized that loss of superoxide dismutase 2 (SOD2) during aging promotes mito-oxidant accumulation in platelets, leading to platelet hyperactivity, and that this phenotype is accentuated by prediabetes. From the Iowa City VA Healthcare System, we recruited 15 young (18-49 year) and 12 middle-aged (50-64 year) Veterans with prediabetes (FBG 100-124 mg/dL and/or HbA1c 5.7-6.4). We also recruited age- and BMI- matched 14 healthy young and 23 middle-aged Veterans. Washed platelets were prepared from whole blood and markers of platelet activation (fibrinogen, activated α II bβ3, and Annexin V) were measured via flowcytometry. Ex vivo , thrombus formation was assessed in a collagen coated microfluidic chamber by measuring accumulation of platelets under arterial shear stress. Expression of SOD2 in platelets measured by western blot was decreased in all three groups vs. young healthy Veterans. Upon agonist activation, platelets from healthy middle-aged Veterans showed only moderate increase in activated αIIbβ3 or fibrinogen and Annexin V binding (P=0.09, P=0.08, and P=0.2 vs. healthy young). Prediabetes caused significant increases in what in both young and middle-aged (main effect of prediabetes, P<0.05 to P<0.01) Veterans. In the flow chamber, platelets from young or middle-aged prediabetics showed greater accumulation (P<0.0001 vs. healthy young or healthy aged). Preincubation of platelets with mitochondria targetable SOD-mimetic, decreased activated αIIbβ3, fibrinogen binding, as well as thrombus formation in both prediabetic groups. We conclude that a prothrombotic state exists in young and middle-aged prediabetics that causes platelet activation and thrombus growth in SOD2-dependent manner. These findings suggest a therapeutic potential of SOD-mimetic in decreasing thrombotic burden in prediabetes.