Effects of a novel hydrogen sulfide prodrug in a porcine model of acute limb ischemia

Amanda M. Rushing, Erminia Donnarumma, David J. Polhemus, Kevin R. Au, Samuel E. Victoria, Jeffrey D. Schumacher, Zhen Li, J. Stephen Jenkins, David J. Lefer, Traci T. Goodchild

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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. Clinical Relevance: In a clinically relevant porcine model of peripheral vascular disease, treatment with a novel hydrogen sulfide prodrug restored ischemic limb blood flow, enhanced circulating hydrogen sulfide and nitrite levels, reduced oxidative stress, and improved ex vivo coronary vascular function via an endothelium-dependent vasodilation mechanism.

Original languageEnglish
Pages (from-to)1924-1935
Number of pages12
JournalJournal of Vascular Surgery
Volume69
Issue number6
DOIs
StatePublished - Jun 2019
Externally publishedYes

Keywords

  • Acute limb ischemia
  • Hydrogen sulfide
  • Nitric oxide
  • Peripheral artery disease
  • Swine

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