Cystathionine-γ-lyase overexpression modulates oxidized nicotinamide adenine dinucleotide biosynthesis and enhances neovascularization

Kevin Kiesworo, MS; Michael R. MacArthur, PhD; Peter Kip, MD, PhD; Thomas Agius, MS; Diane Macabrey, MS; Martine Lambelet, BS; Lauriane Hamard, PhD; C.-Keith Ozaki, MD; James R. Mitchell, PhD; Sébastien Déglise, MD; Sarah J. Mitchell, PhD; Florent Allagnat, PhD; Alban Longchamp, MD, PhD

JVS - Vascular Science (Jan 2023)

Cystathionine-γ-lyase overexpression modulates oxidized nicotinamide adenine dinucleotide biosynthesis and enhances neovascularization

Kevin Kiesworo, MS,
Michael R. MacArthur, PhD,
Peter Kip, MD, PhD,
Thomas Agius, MS,
Diane Macabrey, MS,
Martine Lambelet, BS,
Lauriane Hamard, PhD,
C.-Keith Ozaki, MD,
James R. Mitchell, PhD,
Sébastien Déglise, MD,
Sarah J. Mitchell, PhD,
Florent Allagnat, PhD,
Alban Longchamp, MD, PhD

Affiliations

Kevin Kiesworo, MS: Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
Michael R. MacArthur, PhD: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
Peter Kip, MD, PhD: Department of Surgery and Heart and Vascular Center, Brigham & Women's Hospital and Harvard Medical School, Boston, MA
Thomas Agius, MS: Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
Diane Macabrey, MS: Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
Martine Lambelet, BS: Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
Lauriane Hamard, PhD: Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
C.-Keith Ozaki, MD: Department of Surgery and Heart and Vascular Center, Brigham & Women's Hospital and Harvard Medical School, Boston, MA
James R. Mitchell, PhD: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
Sébastien Déglise, MD: Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
Sarah J. Mitchell, PhD: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
Florent Allagnat, PhD: Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
Alban Longchamp, MD, PhD: Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland; Correspondence: Alban Longchamp, MD, PhD, Department of Vascular Surgery, Lausanne University Hospital, Rue du Bugnon 46, Lausanne 1011, Switzerland

Journal volume & issue: Vol. 4
p. 100095

Abstract

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Objective: Hydrogen sulfide is a proangiogenic gas produced primarily by the transsulfuration enzyme cystathionine-γ-lyase (CGL). CGL-dependent hydrogen sulfide production is required for neovascularization in models of peripheral arterial disease. However, the benefits of increasing endogenous CGL and its mechanism of action have not yet been elucidated. Methods: Male whole body CGL-overexpressing transgenic (CGLTg) mice and wild-type (WT) littermates (C57BL/6J) were subjected to the hindlimb ischemia model (age, 10-12 weeks). Functional recovery was assessed via the treadmill exercise endurance test. Leg perfusion was measured by laser Doppler imaging and vascular endothelial-cadherin immunostaining. To examine the angiogenic potential, aortic ring sprouting assay and postnatal mouse retinal vasculature development studies were performed. Finally, comparative metabolomics analysis, oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) analysis, and quantitative real-time polymerase chain reaction were performed on CGLWT and CGLTg gastrocnemius muscle. Results: The restoration of blood flow occurred more rapidly in CGLTg mice. Compared with the CGLWT mice, the median ± standard deviation running distance and time were increased for the CGLTg mice after femoral artery ligation (159 ± 53 m vs 291 ± 74 m [P 200 million people worldwide and is anticipated to increase with the aging population. In the present study, we outlined the beneficial effects of cystathionine-γ-lyase (CGL) overexpression in improving neovascularization and functional recovery in a murine PAD model. Taken together with other reported studies, our findings further highlight the untapped potential of targeting CGL for therapeutic interventions in patients with PAD.

Published in JVS - Vascular Science

ISSN: 2666-3503 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the circulatory (Cardiovascular) system
Website: https://www.journals.elsevier.com/jvs-vascular-science

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