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.
  
  
  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.
authors.affiliation: Department of Biology, Lakehead University, Thunder Bay, ON, Canada.
authors.forename: Sarathi
authors.initials: S
authors.lastname: Mani
authors.forename: Hongzhu
authors.initials: H
authors.lastname: Li
authors.forename: Ashley
authors.initials: A
authors.lastname: Untereiner
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
authors.forename: Guangdong
authors.initials: G
authors.lastname: Yang
authors.forename: Richard C
authors.initials: RC
authors.lastname: Austin
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Dickhout
authors.forename: Šárka
authors.initials: Š
authors.lastname: Lhoták
authors.forename: Qing H
authors.initials: QH
authors.lastname: Meng
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D003542:Cystathionine gamma-Lyase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006862:Hydrogen Sulfide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013440:Sulfides / Q000494:pharmacology / Q000627:therapeutic use; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D013440:Sulfides; D003542:Cystathionine gamma-Lyase; C025451:sodium bisulfide; D006862:Hydrogen Sulfide
keywords: apolipoprotein E; atherosclerosis; cystathionine γ-lyase; hydrogen sulfide; oxidative stress