PMID- 19858416
OWN - NLM
STAT- MEDLINE
DCOM- 20091207
LR  - 20220311
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Print)
IS  - 0009-7322 (Linking)
VI  - 120
IP  - 19
DP  - 2009 Nov 10
TI  - Hyperhomocysteinemia promotes inflammatory monocyte generation and accelerates 
      atherosclerosis in transgenic cystathionine beta-synthase-deficient mice.
PG  - 1893-902
LID - 10.1161/CIRCULATIONAHA.109.866889 [doi]
AB  - BACKGROUND: Hyperhomocysteinemia (HHcy) is an independent risk factor for 
      cardiovascular disease. Monocytes display inflammatory and resident subsets and 
      commit to specific functions in atherogenesis. In this study, we examined the 
      hypothesis that HHcy modulates monocyte heterogeneity and leads to 
      atherosclerosis. METHODS AND RESULTS: We established a novel 
      atherosclerosis-susceptible mouse model with both severe HHcy and 
      hypercholesterolemia in which the mouse cystathionine beta-synthase (CBS) and 
      apolipoprotein E (apoE) genes are deficient and an inducible human CBS transgene 
      is introduced to circumvent the neonatal lethality of the CBS deficiency (Tg-hCBS 
      apoE(-/-) Cbs(-/-) mice). Severe HHcy accelerated atherosclerosis and 
      inflammatory monocyte/macrophage accumulation in lesions and increased plasma 
      tumor necrosis factor-alpha and monocyte chemoattractant protein-1 levels in 
      Tg-hCBS apoE(-/-) Cbs(-/-) mice fed a high-fat diet. Furthermore, we 
      characterized monocyte heterogeneity in Tg-hCBS apoE(-/-) Cbs(-/-) mice and 
      another severe HHcy mouse model (Tg-S466L Cbs(-/-)) with a disease-relevant 
      mutation (Tg-S466L) that lacks hyperlipidemia. HHcy increased monocyte population 
      and selective expansion of inflammatory Ly-6C(hi) and Ly-6C(mid) monocyte subsets 
      in blood, spleen, and bone marrow of Tg-S466L Cbs(-/-) and Tg-hCBS apoE(-/-) 
      Cbs(-/-) mice. These changes were exacerbated in Tg-S466L Cbs(-/-) mice with 
      aging. Addition of l-homocysteine (100 to 500 micromol/L), but not l-cysteine, 
      maintained the Ly-6C(hi) subset and induced the Ly-6C(mid) subset in cultured 
      mouse primary splenocytes. Homocysteine-induced differentiation of the Ly-6C(mid) 
      subset was prevented by catalase plus superoxide dismutase and the NAD(P)H 
      oxidase inhibitor apocynin. CONCLUSIONS: HHcy promotes differentiation of 
      inflammatory monocyte subsets and their accumulation in atherosclerotic lesions 
      via NAD(P)H oxidase-mediated oxidant stress.
FAU - Zhang, Daqing
AU  - Zhang D
AD  - Department of Pharmacology and Cardiovascular Research Center, Temple University 
      School of Medicine, Philadelphia, PA 19140, USA.
FAU - Jiang, Xiaohua
AU  - Jiang X
FAU - Fang, Pu
AU  - Fang P
FAU - Yan, Yan
AU  - Yan Y
FAU - Song, Jian
AU  - Song J
FAU - Gupta, Sapna
AU  - Gupta S
FAU - Schafer, Andrew I
AU  - Schafer AI
FAU - Durante, William
AU  - Durante W
FAU - Kruger, Warren D
AU  - Kruger WD
FAU - Yang, Xiaofeng
AU  - Yang X
FAU - Wang, Hong
AU  - Wang H
LA  - eng
GR  - R01 HL077288-06/HL/NHLBI NIH HHS/United States
GR  - R01 HL077288/HL/NHLBI NIH HHS/United States
GR  - AHA0555423U/PHS HHS/United States
GR  - HL74966/HL/NHLBI NIH HHS/United States
GR  - R01 HL074966/HL/NHLBI NIH HHS/United States
GR  - HL77288/HL/NHLBI NIH HHS/United States
GR  - R01 HL117654/HL/NHLBI NIH HHS/United States
GR  - HL67033/HL/NHLBI NIH HHS/United States
GR  - HL094451/HL/NHLBI NIH HHS/United States
GR  - R01 HL082774/HL/NHLBI NIH HHS/United States
GR  - R29 HL057299/HL/NHLBI NIH HHS/United States
GR  - R01 DK104116/DK/NIDDK NIH HHS/United States
GR  - HL57299/HL/NHLBI NIH HHS/United States
GR  - HL36045/HL/NHLBI NIH HHS/United States
GR  - R01 HL057299/HL/NHLBI NIH HHS/United States
GR  - R01 HL082774-04/HL/NHLBI NIH HHS/United States
GR  - R01 HL067033/HL/NHLBI NIH HHS/United States
GR  - R01 HL067033-07S1/HL/NHLBI NIH HHS/United States
GR  - HL82774/HL/NHLBI NIH HHS/United States
GR  - R01 HL094451/HL/NHLBI NIH HHS/United States
GR  - R01 HL036045/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20091026
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Apolipoproteins E)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
SB  - IM
MH  - Animals
MH  - Apolipoproteins E/genetics
MH  - Atherosclerosis/*immunology/metabolism/pathology
MH  - Body Weight
MH  - Cells, Cultured
MH  - Chemokine CCL2/blood
MH  - Cystathionine beta-Synthase/*genetics/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Homocystinuria/*immunology/metabolism/pathology
MH  - Humans
MH  - Hyperhomocysteinemia/*immunology/metabolism/pathology
MH  - Macrophages/immunology/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Monocytes/*immunology/pathology
MH  - Oxidative Stress/physiology
MH  - Pregnancy
MH  - Severity of Illness Index
MH  - Spleen/cytology
MH  - Tumor Necrosis Factor-alpha/blood
MH  - Vasculitis/immunology/metabolism/pathology
PMC - PMC2783582
MID - NIHMS153737
EDAT- 2009/10/28 06:00
MHDA- 2009/12/16 06:00
PMCR- 2010/11/10
CRDT- 2009/10/28 06:00
PHST- 2009/10/28 06:00 [entrez]
PHST- 2009/10/28 06:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
PHST- 2010/11/10 00:00 [pmc-release]
AID - CIRCULATIONAHA.109.866889 [pii]
AID - 10.1161/CIRCULATIONAHA.109.866889 [doi]
PST - ppublish
SO  - Circulation. 2009 Nov 10;120(19):1893-902. doi: 
      10.1161/CIRCULATIONAHA.109.866889. Epub 2009 Oct 26.