Abstract P3013: Infusion of Recombinant Human Thioredoxin-1 Completely Protects Against High Fat-Induced Endothelial Dysfunction in Small Mesenteric Arteries From Male C57bl6/j Mice

Abstract

Background: Obesity is a serious risk factor for cardiovascular diseases. A high fat diet results in cellular oxidative stress and endothelial dysfunction in resistance-sized arteries, characterized by reduced nitric oxide (NO) and endothelium-dependent hyperpolarizing (EDH) responses. Thioredoxin-1, an oxidoreductase protein that cleaves disulfide bridges between two adjacent cysteine residues in oxidized proteins, has been shown to lower blood pressure and improve endothelium-dependent relaxing responses in aged C57Bl6/J mice. Methods and Results: Young (~ 3 month-old) male C57Bl6/J mice were fed a high fat diet (42% kcal from fat) or a normal chow. Mice were administered recombinant human thioredoxin-1 (rhTrx1; 1 mg/mL) or saline (0.9% NaCl) via tail vein injection at the start, one- and two months after diet regimen. Body weight (BW) was comparable between lean/rhTrx1 and lean/saline at the time of euthanasia (32 ±1 g versus 32 ± 1 g). The high fat regimen resulted in a comparable BW between obese/saline and obese/rhTrx1 mice (47 ± 1 g versus 45 ± 2 g, respectively). After three months, mice were euthanized and small (second-order branches of the superior) mesenteric arteries were isolated and mounted on the wire-myograph to assess vascular reactivity. Small mesenteric arteries from obese/saline had blunted acetylcholine (10 -9 - 10 -5 M)-mediated relaxations compared to lean/saline mice (pEC 50 5.29 ± 0.27 versus 6.61 ± 0.15, respectively). In obese/rhTrx1 mice, these responses were not statistically significantly different from lean/rhtrx1 mice (pEC 50 6.66 ± 0.25 versus 6.59 ± 0.31, respectively). There were no differences in the sensitivity to the NO donor sodium nitroprusside between the four experimental groups. EDH relaxing responses to the K Ca 3.1 channel opener NS309 (10 -9 - 10 -5.5 M) were blunted in obese/saline compared to lean/saline (pEC 50 6.37 ± 0.12 versus 6.83 ± 0.08). In obese/rhTrx1 mice, these responses were not statistically significantly different from lean/rhTrx1 mice (pEC 50 7.07 ± 0.13 versus 6.63 ± 0.16, respectively). Conclusion: Infusions with rhTrx-1 prevents endothelial dysfunction in obese mice by improving the EDH response.