Abstract 303: Increased Endogenous Hydrogen Sulfide Protects Against Vein Graft Disease

Abstract

Objective: Vein graft failure secondary to intimal hyperplasia remains a challenge. Hydrogen sulfide (H 2 S) is produced endogenously by cystathionine γ-lyase (CGL) in endothelial cells, and as a gasotransmitter holds numerous beneficial vascular effects. We thus hypothesized that increased endogenous H 2 S would attenuate the vascular response to injury. Here, we leveraged a CGL transgenic overexpressing mouse model to test the potential of increased endogenous H 2 S to attenuate the vascular response to injury in a vein graft model. Approach and Results: A murine carotid-interposition cuff technique vein graft model was employed, including an artificial bacterial chromosome-based CGL transgenic (Tg) strain with an extra copy of the CGL gene locus randomly inserted in the genome. CGL Tg mice were fed a high-fat/high-cholesterol diet, implanted with a vein graft from CGL Tg donors (n=8), and compared to wild-type (WT) controls (n=7; WT/ WT conduits); all on C57BL/6 background. Grafts were imaged in vivo with ultrasound biomicropscopy and harvested after 28 days. CGL Tg mice demonstrated an approximate two-fold increase in serum H 2 S production capacity (lead acetate assay) compared to controls. The CGL Tg mice exhibited a significant decrease in their intimal thickness (p=<0.05, Fig.A) and intimal/medial+adventia ratios (p=<0.05, Fig.B) 28 days after implantation. In vivo biomicroscopy was supportive: CGL tg mice had a larger mean luminal diameter relative to WT controls (p=<0.05, Fig.C). Conclusion: Elevated endogenous H 2 S production reduces the fibroproliferative response to vein graft arterialization. Manipulation of this gasotransmitter’s biology stands as a novel approach to impact the durability of vascular reconstructions.