Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis

Sarathi Mani, Hongzhu Li, Ashley Untereiner, Lingyun Wu, Guangdong Yang, Richard C. Austin, Jeffrey G. Dickhout, Šárka Lhoták, Qing H. Meng, Rui Wang

Research output: Contribution to journalArticle

169 Citations (Scopus)

Abstract

Background-Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H2S) in the cardiovascular system. The deficiency of CSE in mice leads to a decreased endogenous H2S 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 H2S 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 H2S protects vascular tissues from atherogenic damage by reducing vessel intimal proliferation and inhibiting adhesion molecule expression. Decreased endogenous H2S production predisposes the animals to vascular remodeling and early development of atherosclerosis. The CSE/H2S pathway is an important therapeutic target for protection against atherosclerosis.

Original languageEnglish (US)
Pages (from-to)2523-2534
Number of pages12
JournalCirculation
Volume127
Issue number25
DOIs
StatePublished - Jun 25 2013
Externally publishedYes

Fingerprint

Cystathionine
Hydrogen Sulfide
Lyases
Atherosclerosis
Knockout Mice
Tunica Intima
Atherogenic Diet
Apolipoproteins E
Oxidative Stress
Blood Pressure
Hyperhomocysteinemia
Gene Knockout Techniques
Acetylcysteine
Cell Adhesion Molecules
Homocysteine
Cardiovascular System
Vasodilation
LDL Cholesterol
Endothelium
Blood Vessels

Keywords

  • apolipoprotein E
  • atherosclerosis
  • cystathionine .-lyase
  • hydrogen sulfide
  • oxidative stress

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Mani, S., Li, H., Untereiner, A., Wu, L., Yang, G., Austin, R. C., ... Wang, R. (2013). Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. Circulation, 127(25), 2523-2534. https://doi.org/10.1161/CIRCULATIONAHA.113.002208

Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. / Mani, Sarathi; Li, Hongzhu; Untereiner, Ashley; Wu, Lingyun; Yang, Guangdong; Austin, Richard C.; Dickhout, Jeffrey G.; Lhoták, Šárka; Meng, Qing H.; Wang, Rui.

In: Circulation, Vol. 127, No. 25, 25.06.2013, p. 2523-2534.

Research output: Contribution to journalArticle

Mani, S, Li, H, Untereiner, A, Wu, L, Yang, G, Austin, RC, Dickhout, JG, Lhoták, Š, Meng, QH & Wang, R 2013, 'Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis', Circulation, vol. 127, no. 25, pp. 2523-2534. https://doi.org/10.1161/CIRCULATIONAHA.113.002208
Mani S, Li H, Untereiner A, Wu L, Yang G, Austin RC et al. Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. Circulation. 2013 Jun 25;127(25):2523-2534. https://doi.org/10.1161/CIRCULATIONAHA.113.002208
Mani, Sarathi ; Li, Hongzhu ; Untereiner, Ashley ; Wu, Lingyun ; Yang, Guangdong ; Austin, Richard C. ; Dickhout, Jeffrey G. ; Lhoták, Šárka ; Meng, Qing H. ; Wang, Rui. / Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. In: Circulation. 2013 ; Vol. 127, No. 25. pp. 2523-2534.
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title = "Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis",
abstract = "Background-Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H2S) in the cardiovascular system. The deficiency of CSE in mice leads to a decreased endogenous H2S 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 H2S 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 H2S protects vascular tissues from atherogenic damage by reducing vessel intimal proliferation and inhibiting adhesion molecule expression. Decreased endogenous H2S production predisposes the animals to vascular remodeling and early development of atherosclerosis. The CSE/H2S pathway is an important therapeutic target for protection against atherosclerosis.",
keywords = "apolipoprotein E, atherosclerosis, cystathionine .-lyase, hydrogen sulfide, oxidative stress",
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AU - Mani, Sarathi

AU - Li, Hongzhu

AU - Untereiner, Ashley

AU - Wu, Lingyun

AU - Yang, Guangdong

AU - Austin, Richard C.

AU - Dickhout, Jeffrey G.

AU - Lhoták, Šárka

AU - Meng, Qing H.

AU - Wang, Rui

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Y1 - 2013/6/25

N2 - Background-Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H2S) in the cardiovascular system. The deficiency of CSE in mice leads to a decreased endogenous H2S 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 H2S 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 H2S protects vascular tissues from atherogenic damage by reducing vessel intimal proliferation and inhibiting adhesion molecule expression. Decreased endogenous H2S production predisposes the animals to vascular remodeling and early development of atherosclerosis. The CSE/H2S pathway is an important therapeutic target for protection against atherosclerosis.

AB - Background-Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H2S) in the cardiovascular system. The deficiency of CSE in mice leads to a decreased endogenous H2S 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 H2S 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 H2S protects vascular tissues from atherogenic damage by reducing vessel intimal proliferation and inhibiting adhesion molecule expression. Decreased endogenous H2S production predisposes the animals to vascular remodeling and early development of atherosclerosis. The CSE/H2S pathway is an important therapeutic target for protection against atherosclerosis.

KW - apolipoprotein E

KW - atherosclerosis

KW - cystathionine .-lyase

KW - hydrogen sulfide

KW - oxidative stress

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