Abstract 5044: Aldose Reductase-Dependent Effects on Endothelial Dysfunction and Endothelial Progenitor Cells in Diet-Induced Obesity
Chronic diabetes increases cardiovascular disease risk. Long-term hyperglycemia in diabetes increases non-glycolytic consumption of glucose via the polyol pathway, which has been linked to the development of secondary diabetic complications. To examine the contribution of this pathway, wild-type (WT; C57BL/6) mice and mice deficient in aldose reductase (AR-null), an enzyme catalyzing the first step of the pathway, were fed normal chow (NC, 13.5 % kcal fat) or a high-fat diet (HFD, 42% kcal fat) for 12 weeks. In comparison with WT mice (n=12), AR-null (n=12) mice gained significantly more weight (+14.9±0.9 g vs. +20.8±1.1 g; P<0.05) and displayed greater increase in plasma cholesterol (+133±213 mg/dl vs. +194±17 mg/dl; P<0.05) and insulin (+0.40±0.11 vs. +0.57±0.07 ng/ml; P<0.05). Insulin (100 nM) exposure increased Akt phosphorylation in isolated aorta of WT NC mice but not of AR-null mice (see figure⇓). Aorta isolated from HFD WT and AR-null mice were insulin-insensitive. High-fat feeding decreased acetylcholine-induced relaxation of aorta measured ex vivo in AR-null mice by 25±4 % (P<0.05, n=12) but not in WT mice. High fat feeding decreased the levels of Sca+/Flk+ endothelial progenitor cells (EPCs) in the peripheral blood (per 50,000 events: 197±79 vs. 103±19; P<0.05) yet increased EPCs in spleen (812±456 vs. 2088±1173; P<0.05) and bone marrow (432±269 vs. 1031±658; P<0.05) in WT mice. These changes were absent in AR-null mice. Collectively, these data suggest that AR-dependent metabolism during pre-diabetic conditions plays a significant role in the maintenance of endothelial health perhaps through impaired insulin signaling and trafficking of EPCs.