Tail Vein Injections of Recombinant Human Thioredoxin Prevents High Fat-induced Endothelial Dysfunction in Mice

Abstract BackgroundObesity 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, a sulfo-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 ResultsYoung (～ 3 month-old) male C57Bl6/J mice were fed a high fat diet (42% kcal from fat; obese) or a normal chow (lean) for 3 months. Mice were administered recombinant human thioredoxin-1 (rhTrx; 25 mg/kg) or saline (0.9% NaCl) via tail vein injection at the start, after one month, and after two months. 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/rhTrx mice (47 ± 1 g versus 45 ± 2 g, respectively). Small (second-order branches) mesenteric arteries (MA2), coronary and femoral arteries were isolated and mounted on the wire-myograph. MA2 and femoral arteries from obese/saline had blunted acetylcholine (10?9 – 10?5 M)-mediated relaxations compared to lean/saline mice, but not to the NO donor sodium nitroprusside. NO and EDH-mediated relaxing responses were blunted in MA2 from obese/lean mice compared to the three other groups. ConclusionTail vein injections with rhTrx prevented endothelial dysfunction in obese mice by improving NO and EDH relaxing responses in MA2.