Amanda M Rushing1, Erminia Donnarumma1, David J Polhemus2, Kevin R Au3, Samuel E Victoria3, Jeffrey D Schumacher4, Zhen Li2, J Stephen Jenkins5, David J Lefer2, Traci T Goodchild6. 1. Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center-New Orleans, New Orleans, La. 2. Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center-New Orleans, New Orleans, La; Department of Pharmacology, Louisiana State University Health Sciences Center-New Orleans, New Orleans, La. 3. Department of Vascular Surgery, Louisiana State University Health Sciences Center-New Orleans, New Orleans, La. 4. Department of Animal Care, Louisiana State University Health Sciences Center-New Orleans, New Orleans, La. 5. Heart and Vascular Institute, Ochsner Medical Center, New Orleans, La. 6. Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center-New Orleans, New Orleans, La; Department of Pharmacology, Louisiana State University Health Sciences Center-New Orleans, New Orleans, La. Electronic address: tgoodc@lsuhsc.edu.
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 μmol/L vs 1.8 ± 0.50 μmol/L; P < .05), sulfane sulfur (10.6 ± 2.3 μmol/L vs 2.6 ± 0.8 μmol/L; P < .05), and nitrite (0.5 ± 0.05 μmol/L vs 0.3 ± 0.03 μmol/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/mm2 vs 79.0 ± 9.8 capillaries/mm2; 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.
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 μmol/L vs 1.8 ± 0.50 μmol/L; P < .05), sulfane sulfur (10.6 ± 2.3 μmol/L vs 2.6 ± 0.8 μmol/L; P < .05), and nitrite (0.5 ± 0.05 μmol/L vs 0.3 ± 0.03 μmol/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/mm2 vs 79.0 ± 9.8 capillaries/mm2; 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.
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