title: Increased plasma S-adenosyl-homocysteine levels induce the proliferation and migration of VSMCs through an oxidative stress-ERK1/2 pathway in apoE(-/-) mice.
abstract: OBJECTIVE
  Although S-adenosyl-homocysteine (SAH) is considered to be a more sensitive predictor of cardiovascular disease than homocysteine, the underlying mechanisms of its effects remain unknown. We investigated the in vivo and in vitro effects of SAH on vascular smooth muscle cells (VSMCs) proliferation and migration related to the development of atherogenesis in apolipoprotein E-deficient (apoE(-/-)) mice.
  
  
  RESULTS
  A total of 72 apoE(-/-) mice were randomly divided into six groups (n= 12 for each group). The control group was fed a conventional diet, the M group was fed a 1% methionine-supplemented diet, the A group was fed a diet that was supplemented with the SAH hydrolase (SAHH) inhibitor adenosine-2, 3-dialdehyde (ADA), the M+A group was fed a diet that was supplemented with methionine plus ADA, and two of the groups were intravenously injected with retrovirus that expressed either SAHH shRNA (SAHH(+/-)) or scrambled shRNA semi-weekly for 8 weeks. Compared with the controls, the mice in the A, M+A, and SAHH(+/-) groups had higher plasma SAH levels, larger atheromatous plaques, elevated VSMC proliferation, and higher aortic reactive oxygen species and malondialdehyde levels. In cultured VSMCs, 5 μM ADA or SAHH shRNA caused SAH accumulation, which resulted in increased cell proliferation, migration, oxidative stress, and extracellular-regulated kinase 1/2 (ERK1/2) activation. These effects were significantly attenuated by preincubation with superoxide dismutase (300 U/mL).
  
  
  CONCLUSIONS
  Our results suggest that elevated SAH induces VSMC proliferation and migration through an oxidative stress-dependent activation of the ERK1/2 pathway to promote atherogenesis.
authors.affiliation: Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health,  Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou 510080,  PR China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Luo
authors.forename: Yunjun
authors.initials: Y
authors.lastname: Xiao
authors.forename: Fenglin
authors.initials: F
authors.lastname: Song
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.forename: Wenhua
authors.initials: W
authors.lastname: Ling
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019587:Dietary Supplements / Q000009:adverse effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008715:Methionine / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D012435:S-Adenosylhomocysteine / Q000097:blood* / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D012435:S-Adenosylhomocysteine; D008715:Methionine