PMID- 22912384
OWN - NLM
STAT- MEDLINE
DCOM- 20130107
LR  - 20220317
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Linking)
VI  - 111
IP  - 10
DP  - 2012 Oct 26
TI  - Hyperhomocysteinemia exaggerates adventitial inflammation and angiotensin 
      II-induced abdominal aortic aneurysm in mice.
PG  - 1261-73
LID - 10.1161/CIRCRESAHA.112.270520 [doi]
AB  - RATIONALE: A number of epidemiological studies have suggested an association of 
      hyperhomocysteinemia (HHcy) and abdominal aortic aneurysm (AAA), but 
      discrepancies exist. In addition, we lack direct evidence supporting a causal 
      role. OBJECTIVE: We determined the association and contribution of HHcy to AAA 
      formation. METHODS AND RESULTS: We first performed a meta-analysis of studies 
      involving 1489 subjects and found a strong association of HHcy and AAA (odds 
      ratio, 7.39). Next, we used angiotensin II-infused male apolipoprotein 
      E-deficient mice and tested whether HHcy contributes to AAA pathogenesis. 
      Homocysteine (Hcy) supplement (1.8 g/L) in drinking water resulted in mild HHcy. 
      Intriguingly, HHcy greatly increased the incidence of angiotensin II-induced AAA 
      and aortic dissection in apolipoprotein E-deficient mice (vehicle versus Hcy: 50% 
      versus 100%; P<0.05). Histology indicated HHcy markedly exaggerated aortic 
      adventitial inflammation. Increased levels of proinflammatory interleukin-6 and 
      monocyte chemoattractant protein-1 were preferentially colocalized within 
      adventitial fibroblasts in HHcy plus angiotensin II mice, which suggested the 
      importance of adventitial fibroblasts activation in Hcy-aggravated AAA. Hcy 
      sequentially stimulated adventitial fibroblasts transformation into 
      myofibroblasts, secretion of interleukin-6 and monocyte chemoattractant 
      protein-1, and consequent recruitment of monocytes/macrophages to adventitial 
      fibroblasts, which was abolished by the NADPH oxidase inhibitor diphenyliodonium. 
      NADPH oxidase 4, but not other homologs of NADPH oxidase, was significantly 
      upregulated by Hcy in adventitial fibroblasts, whereas NADPH oxidase 4 small 
      interfering RNA silencing diminished Hcy-induced adventitial fibroblasts 
      activation. Finally, folic acid supplement (0.071 mug/g per day) markedly reduced 
      HHcy-aggravated angiotensin II-induced AAA formation in apolipoprotein 
      E-deficient mice. CONCLUSIONS: HHcy may aggravate AAA formation at least 
      partially via activating adventitial fibroblast NADPH oxidase 4.
FAU - Liu, Ziyi
AU  - Liu Z
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Beijing 100191, China .
FAU - Luo, Hongzhi
AU  - Luo H
FAU - Zhang, Lu
AU  - Zhang L
FAU - Huang, Yaqian
AU  - Huang Y
FAU - Liu, Bo
AU  - Liu B
FAU - Ma, Kongyang
AU  - Ma K
FAU - Feng, Juan
AU  - Feng J
FAU - Xie, Jinsheng
AU  - Xie J
FAU - Zheng, Jingang
AU  - Zheng J
FAU - Hu, Jing
AU  - Hu J
FAU - Zhan, Siyan
AU  - Zhan S
FAU - Zhu, Yi
AU  - Zhu Y
FAU - Xu, Qingbo
AU  - Xu Q
FAU - Kong, Wei
AU  - Kong W
FAU - Wang, Xian
AU  - Wang X
LA  - eng
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
DEP - 20120821
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Apolipoproteins E)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-6)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Smad2 Protein)
RN  - 0 (Smad2 protein, mouse)
RN  - 0 (Smad3 Protein)
RN  - 0 (Smad3 protein, mouse)
RN  - 0 (Vasoconstrictor Agents)
RN  - 11128-99-7 (Angiotensin II)
RN  - EC 1.6.3.- (NADPH Oxidase 4)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.- (Nox4 protein, mouse)
SB  - IM
MH  - Adventitia/immunology
MH  - Angiotensin II/pharmacology
MH  - Animals
MH  - Aortic Aneurysm, Abdominal/chemically induced/*epidemiology/*immunology
MH  - Apolipoproteins E/genetics
MH  - Chemokine CCL2/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Fibroblasts/enzymology/immunology/metabolism
MH  - Humans
MH  - Hyperhomocysteinemia/*epidemiology/*immunology/metabolism
MH  - Incidence
MH  - Interleukin-6/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Middle Aged
MH  - NADPH Oxidase 4
MH  - NADPH Oxidases/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Risk Factors
MH  - Signal Transduction/immunology
MH  - Smad2 Protein/metabolism
MH  - Smad3 Protein/metabolism
MH  - Vasculitis/*epidemiology/*immunology/metabolism
MH  - Vasoconstrictor Agents/pharmacology
EDAT- 2012/08/23 06:00
MHDA- 2013/01/08 06:00
CRDT- 2012/08/23 06:00
PHST- 2012/08/23 06:00 [entrez]
PHST- 2012/08/23 06:00 [pubmed]
PHST- 2013/01/08 06:00 [medline]
AID - CIRCRESAHA.112.270520 [pii]
AID - 10.1161/CIRCRESAHA.112.270520 [doi]
PST - ppublish
SO  - Circ Res. 2012 Oct 26;111(10):1261-73. doi: 10.1161/CIRCRESAHA.112.270520. Epub 
      2012 Aug 21.