Rushing, Amanda M.; Donnarumma, Erminia; Polhemus, David J.; Au, Kevin R.; Victoria, Samuel E.; Schumacher, Jeffrey D.; Li, Zhen; Jenkins, J. Stephen; Lefer, David J.; Goodchild, Traci T.
Abstract
Objective: Previous studies have shown that hydrogen sulfide (H2S) exerts potent proangiogenic properties under in vitro conditions and in rodent models. We sought to determine whether a novel H2S prodrug promotes peripheral revascularization in a swine model of acute limb ischemia (ALI).; Methods: ALI was induced in 17 female miniswine via intravascular occlusion of the external iliac. At day 7 after ALI induction, miniswine (n = 17) were randomized to received placebo or the H2S prodrug, SG-1002 (800 mg per os twice a day), for 35 days. At day 35 SG-1002 increased circulating levels of H2S (5.0 +/- 1.2 mu mol/L vs 1.8 +/- 0.50 mu mol/L; P < .05), sulfane sulfur (10.6 +/- 2.3 mu mol/L vs 2.6 +/- 0.8 mu mol/L; P < .05), and nitrite (0.5 +/- 0.05 mu mol/L vs 0.3 +/- 0.03 mu mol/L; P < .005) compared with placebo. SG-1002 therapy increased angiographic scoring in ischemic limb vessel number (27.6 +/- 1.6 vs 22.2 +/- 1.8; P < .05) compared with placebo. Treatment with SG-1002 preserved existing capillaries in ischemic limbs (128.3 +/- 18.7 capillaries/mm(2) vs 79.0 +/- 9.8 capillaries/mm(2); P < .05) compared with placebo. Interestingly, treatment with SG-1002 also improved coronary vasorelaxation responses to bradykinin and substance P in miniswine with ALI.; Conclusions: Our results suggest that daily administration of the H2S prodrug, SG-1002, leads to an increase in circulating H2S and nitric oxide signaling and preserves vessel number and density in ischemic limbs. Furthermore, SG-1002 therapy improved endothelial-dependent coronary artery vasorelaxation in the setting of ALI. Our data demonstrate that SG-1002 preserves the vascular architecture in ischemic limbs and exerts vascular protective effects in the coronary vasculature in a model of peripheral vascular disease.
