Decreased Endogenous Production of Hydrogen Sulfide Accelerates Atherosclerosis
Open accessAbstract
Background—: Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H 2 S) in the cardiovascular system. The deficiency of CSE in mice leads to a decreased endogenous H 2 S level, an age-dependent increase in blood pressure, and impaired endothelium-dependent vasorelaxation. To date, there is no direct evidence for a causative role of altered metabolism of endogenous H 2 S in atherosclerosis development. Methods and Results—: Six-week-old CSE gene knockout and wild-type mice were fed with either a control chow or atherogenic paigen-type diet for 12 weeks. Plasma lipid profile and homocysteine levels, blood pressure, oxidative stress, atherosclerotic lesion size in the aortic roots, cell proliferation, and adhesion molecule expression were then analyzed. CSE-knockout mice fed with atherogenic diet developed early fatty streak lesions in the aortic root, elevated plasma levels of cholesterol and low-density lipoprotein cholesterol, hyperhomocysteinemia, increased lesional oxidative stress and adhesion molecule expression, and enhanced aortic intimal proliferation. Treatment of CSE-knockout mice with NaHS, but not N -acetylcysteine or ezetimibe, inhibited the accelerated atherosclerosis development. Double knockout of CSE and apolipoprotein E gene expression in mice exacerbated atherosclerosis development more than that in the mice with only apolipoprotein E or CSE knockout. Conclusions—: Endogenously synthesized H 2 S protects vascular tissues from atherogenic damage by reducing vessel intimal proliferation and inhibiting adhesion molecule expression. Decreased endogenous H 2 S production predisposes the animals to vascular remodeling and early development of atherosclerosis. The CSE/H 2 S pathway is an important therapeutic target for protection against atherosclerosis.
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The H2S donor sodium hydrosulfide reduces atherosclerosis in Apoe-knockout mice, whereas genetic targeting of the H2S synthesizing enzyme cystathionine γ-lyase exacerbates atherosclerosis in this model.
“The H2S donor sodium hydrosulfide reduces atherosclerosis in Apoe -knockout mice132, whereas genetic targeting of the H2S synthesizing enzyme cystathionine γ-lyase exacerbates atherosclerosis in this model98.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [98]
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Self-citation
- Authors
- Mani, S., Li, H., Untereiner, A., Wu, L., Yang, G., Austin, R. C., Dickhout, J. G., Lhoták, Š., Meng, Q. H., & Wang, R.
- Affiliations
- University of Saskatchewan (CA)
- ORCID
- Venue
- Circulation
- Published
- 2013-06-25
- Volume
- 127
- Issue
- 25
- Pages
- 2523-2534
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2153365782
- Cited by
- 377
- References
- 45
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 23 · 2023: 24 · 2022: 31 · 2021: 38 · 2020: 37 · 2019: 33 · 2018: 25 · 2017: 36 · 2016: 22 · 2015: 39 · 2014: 35 · 2013: 3
- FWCI
- 15.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- Canadian Institutes of Health Research (119565_1, 74477, MOP-74477)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- hydrogen sulfide, cystathionine gamma-lyase, atherosclerosis, atherogenic diet, hyperhomocysteinemia, oxidative stress, adhesion molecules, intimal proliferation, apolipoprotein E, sodium hydrosulfide, vascular remodeling, plasma lipids
- MeSH terms
- Animals, Apolipoproteins E, Cystathionine gamma-Lyase, Disease Models, Animal, Hydrogen Sulfide, Male, Mice, Inbred C57BL, Sulfides, Signal Transduction, Tunica Intima, Mice, Knockout, Oxidative Stress, Cell Proliferation, Atherosclerosis, Mice
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