Abstract 886: Mitochondrial Oxidative Stress Negatively Impacts Endothelial Function in the Metabolic Syndrome
The prediabetic metabolic syndrome (pdMS) is characterized by modest to moderate impairments of endothelial function that progress to severe dysfunction as the disease evolves to Type II diabetes. Although in diabetes mitochondrial oxidative stress (mtOxStress) is postulated to contribute to diabetic cardiomyopathy, a link between mtOxStress and endothelial dysfunction in diabetes or in the pdMS is undetermined. Because mitochondrial (mt) DNA fragmentation occurs with mtOxStress, and such effects will alter expression of key mitochondrial proteins involved with energy production and cell viability, we hypothesized that in the pdMS, mtOxStress leading to mtDNA fragmentation, alters endothelial function impairing endothelium-dependent dilation. To test this, lean (LN, n = 6) and obese (OB, n = 11) Zucker fatty rats (model of pdMS) were instrumented with a jugular catheter to deliver recombinant proteins (mt-tat-ExoIII [0.2 ug/g/day]: TAT sequence to enable intracellular delivery, a mt-localization sequence, and the bacterial exonuclease, ExoIII, to fragment mtDNA; or mt-tat-EndoIII [0.25– 0.5 ug/g/day]: TAT sequence + mt-localization sequence + DNA repair enzyme Endo III to repair mtDNA) iv for 24 hrs prior to study. Controls were treated with vehicle. Endothelial dependent (acetylcholine, ACH), and independent (sodium nitroprusside, SNP) vasodilation was determined in isolated, cannulated mesenteric small arteries (mean diameter = 210 um). Dose-response (D-R) curves to SNP were similar in all groups and treatments suggesting that smooth muscle function was unaffected by the treatments or the pdMS. In LN controls, ACH produced dose-dependent dilation (maximal response = 99 ± 1% dilation). In LN, mtDNA fragmentation by mt-tat-ExoIII right-shifted the entire ACH D-R curve and depressed the maximal response (90 ± 2% dilation, P < 0.05 vs LN control). In OB controls, dilation to ACH was less than LN (maximal response = 82 ± 2% dilation, P < 0.05), but vasodilation in OB was completely restored to LN control levels by mtDNA repair with mt-tat-EndoIII (100 ± 1% dilation, P < 0.05 vs OB control, P = NS vs LN). We conclude that mtOxStress, and its effects on mtDNA integrity, play key roles in endothelial dysfunction in the prediabetic metabolic syndrome.