Short-Term Preoperative Protein Restriction Attenuates Vein Graft Disease via Induction of Cystathionine ϒ-Lyase

AIMS: Therapies to prevent vein graft disease, a major problem in cardiovascular and lower extremity bypass surgeries, are currently lacking. Short-term preoperative protein restriction holds promise as an effective preconditioning method against surgical stress in rodent models, but whether it can improve vein graft patency after bypass surgery is undetermined. Here, we hypothesized that short-term protein restriction would limit vein graft disease via upregulation of cystathionine-gamma-lyase and increased endogenous production of the cytoprotective gaseous signaling molecule hydrogen sulfide. METHODS AND RESULTS: Low-density lipoprotein receptor knockout mice were preconditioned for one week on a high-fat high-cholesterol diet with or without protein prior to left common carotid interposition vein graft surgery with caval veins from donor mice on corresponding diets. Both groups were returned to a complete high-fat high-cholesterol diet postoperatively, and vein grafts analyzed 4 or 28 days later. A novel global transgenic cystathionine-gamma-lyase overexpressing mouse model was also employed to study effects of genetic overexpression on graft patency. Protein restriction decreased vein graft intimal/media+adventitia area and thickness ratios, intimal smooth muscle cell infiltration 28 days postoperatively, and neutrophil transmigration 4 days postoperatively. Protein restriction increased cystathionine-gamma-lyase protein expression in aortic and caval vein endothelial cells and percentage of lung endothelial cell producing hydrogen sulfide. The cystathionine-gamma-lyase inhibitor propargylglycine abrogated protein restriction-mediated protection from graft failure and the increase in hydrogen sulfide-producing endothelial cells, while cystathionine-gamma-lyase transgenic mice displayed increased hydrogen sulfide production capacity and were protected from vein graft disease independent of diet. CONCLUSION(S): One week of protein restriction attenuates vein graft disease via increased cystathionine-gamma-lyase expression and hydrogen sulfide production, and decreased early inflammation. Dietary or pharmacological interventions to increase cystathionine-gamma-lyase or hydrogen sulfide may thus serve as new and practical strategies to improve vein graft durability.